U.S. patent application number 13/806048 was filed with the patent office on 2013-08-15 for 2-quinolinyl-acetic acid derivatives as hiv antiviral compounds.
This patent application is currently assigned to GILEAD SCIENCES, INC.. The applicant listed for this patent is Kerim Babaoglu, Kyla Bjornson, Hongyan Guo, Randall L. Halcomb, John O. Link, Hongtao Liu, Michael L. Mitchell, Jianyu Sun, James Taylor, Randall W. Vivian, Lianhong Xu. Invention is credited to Kerim Babaoglu, Kyla Bjornson, Hongyan Guo, Randall L. Halcomb, John O. Link, Hongtao Liu, Michael L. Mitchell, Jianyu Sun, James Taylor, Randall W. Vivian, Lianhong Xu.
Application Number | 20130210801 13/806048 |
Document ID | / |
Family ID | 44508471 |
Filed Date | 2013-08-15 |
United States Patent
Application |
20130210801 |
Kind Code |
A1 |
Babaoglu; Kerim ; et
al. |
August 15, 2013 |
2-QUINOLINYL-ACETIC ACID DERIVATIVES AS HIV ANTIVIRAL COMPOUNDS
Abstract
The invention provides compounds of formula (I): or a salt
thereof as described herein. The invention also provides
pharmaceutical compositions comprising a compound of formula (I),
processes for preparing compounds of formula (I), intermediates
useful for preparing compounds of formula I and therapeutic methods
for treating the proliferation of the HIV virus, treating AIDS or
delaying the onset of AIDS or ARC symptoms in a mammal using
compounds of formula (I). ##STR00001##
Inventors: |
Babaoglu; Kerim; (Lansdale,
PA) ; Bjornson; Kyla; (San Mateo, CA) ; Guo;
Hongyan; (San Mateo, CA) ; Halcomb; Randall L.;
(Foster City, CA) ; Link; John O.; (San Francisco,
CA) ; Liu; Hongtao; (Cupertino, CA) ;
Mitchell; Michael L.; (Hayward, CA) ; Sun;
Jianyu; (Burnaby, CA) ; Taylor; James; (San
Mateo, CA) ; Vivian; Randall W.; (San Mateo, CA)
; Xu; Lianhong; (Palo Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Babaoglu; Kerim
Bjornson; Kyla
Guo; Hongyan
Halcomb; Randall L.
Link; John O.
Liu; Hongtao
Mitchell; Michael L.
Sun; Jianyu
Taylor; James
Vivian; Randall W.
Xu; Lianhong |
Lansdale
San Mateo
San Mateo
Foster City
San Francisco
Cupertino
Hayward
Burnaby
San Mateo
San Mateo
Palo Alto |
PA
CA
CA
CA
CA
CA
CA
CA
CA
CA |
US
US
US
US
US
US
US
CA
US
US
US |
|
|
Assignee: |
GILEAD SCIENCES, INC.
Foster City
CA
|
Family ID: |
44508471 |
Appl. No.: |
13/806048 |
Filed: |
July 1, 2011 |
PCT Filed: |
July 1, 2011 |
PCT NO: |
PCT/US2011/042881 |
371 Date: |
April 26, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61361335 |
Jul 2, 2010 |
|
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|
Current U.S.
Class: |
514/210.21 ;
514/230.2; 514/230.5; 514/235.2; 514/291; 514/311; 514/314;
544/101; 544/105; 544/128; 546/169; 546/170; 546/173; 546/89 |
Current CPC
Class: |
C07D 491/052 20130101;
C07D 215/38 20130101; C07D 498/04 20130101; C07D 215/227 20130101;
C07D 401/04 20130101; C07D 487/04 20130101; C07D 413/04 20130101;
C07D 417/04 20130101; C07D 215/06 20130101; C07D 215/14 20130101;
C07D 215/48 20130101; C07D 215/18 20130101; C07D 401/12 20130101;
C07D 215/20 20130101; C07D 519/00 20130101; C07D 405/04 20130101;
A61P 31/18 20180101 |
Class at
Publication: |
514/210.21 ;
546/173; 514/311; 514/314; 546/170; 546/169; 546/89; 514/291;
544/128; 514/235.2; 544/105; 514/230.5; 544/101; 514/230.2 |
International
Class: |
C07D 498/04 20060101
C07D498/04; C07D 215/48 20060101 C07D215/48; C07D 491/052 20060101
C07D491/052; C07D 215/14 20060101 C07D215/14 |
Claims
1. A compound of formula I: ##STR00252## wherein: G.sup.1 is N,
G.sup.2 is CR.sup.8, and the dashed bond is a double bond; or
G.sup.1 is CR.sup.5, G.sup.2 is N, and the dashed bond is a double
bond; or G.sup.1 is CR.sup.5, G.sup.2 is NR.sup.13, the dashed bond
is a single bond, and R.sup.7 is an oxo (.dbd.O) group; or G.sup.1
is CR.sup.5, G.sup.2 is NR.sup.13, the dashed bond is a single
bond, and R.sup.7 and R.sup.13 together with the atoms to which
they are attached form a heteroaryl, wherein the heteroaryl is
optionally substituted with one or more Z.sup.1 groups; R.sup.1 is
R.sup.1a or R.sup.1b; R.sup.2 is R.sup.2a or R.sup.2b; R.sup.3 is
R.sup.3a or R.sup.3b; R.sup.3' is R.sup.3a' or R.sup.3b'; R.sup.4
is R.sup.4a or R.sup.4b; R.sup.5 is R.sup.5a or R.sup.5b; R.sup.6
is R.sup.6a or R.sup.6b; R.sup.7 is R.sup.7a or R.sup.7b; R.sup.8
is R.sup.8a or R.sup.8b; R.sup.13 is R.sup.13a or R.sup.13b;
R.sup.1a is selected from: a) H, halo, (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl; b) (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)cycloalkyl, nitro,
cyano, aryl, heterocycle and heteroaryl; c) --C(O)--R.sup.11,
--SO.sub.2--R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11, --(C.sub.1-C.sub.6)alkyl-S
--R.sup.11, --(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and d) --N(R.sup.9)R.sup.10,
--C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and wherein any aryl, heterocycle or
heteroaryl of R.sup.1a is optionally substituted with one or more
Z.sup.10 groups; R.sup.1b is selected from: a)
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.3-C.sub.7)halocarbocycle,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl, either alone or as part of a group, is
optionally substituted with one or more Z.sup.1 groups; b)
spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle is
optionally substituted with one or more Z.sup.1 groups, wherein two
Z.sup.1 groups together with the atom or atoms to which they are
attached optionally form a (C.sub.3-C.sub.7)carbocycle or
heterocycle, wherein the (C.sub.3-C.sub.7)carbocycle or heterocycle
is optionally substituted with one or more Z.sup.1 groups; c)
(C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups; d)
--X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl and --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more Z.sup.3 groups and optionally
substituted with one or more Z.sup.1 groups, and wherein any
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, is substituted with one or more
Z.sup.4 groups and optionally substituted with one or more Z.sup.1
groups; e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl
and --Xheterocycle, wherein any aryl heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups; f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups; and g)
--NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f, --OC(O)NR.sub.eR.sub.f,
--SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein each any
(C.sub.1-C.sub.6)alkyl, as part of a group, is optionally
substituted with one or more Z.sup.1 groups; R.sup.2a is selected
from: a) H, (C.sub.1-C.sub.6)alkyl and --O(C.sub.1-C.sub.6)alkyl;
b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle, heteroaryl, halo, nitro and cyano; c)
--C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl and
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more
Z.sup.11 groups; d) --OH, --O(C.sub.2-C.sub.6)alkenyl,
--O(C.sub.2-C.sub.6)alkynyl, --O(C.sub.1-C.sub.6)haloalkyl,
--O(C.sub.3-C.sub.7)cycloalkyl, --Oaryl, --Oheterocycle and
--Oheteroaryl; and e) --N(R.sup.9)R.sup.10,
--C(.dbd.O)--N(R.sup.9)R.sup.10, --O--C(.dbd.)--N(R.sup.9)R.sup.10,
--SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10, and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; R.sup.2b is selected from: a)
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13--(C.sub.1--
C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z'',
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.1i,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.3-C.sub.7)halocarbocycle,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl, either alone or as part of a group, is
optionally substituted with one or more Z.sup.1 groups; b)
spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle is
optionally substituted with one or more Z.sup.1 groups, and wherein
two Z.sup.1 groups together with the atom or atoms to which they
are attached optionally form a (C.sub.3-C.sub.7)carbocycle or
heterocycle, wherein the (C.sub.3-C.sub.7)carbocycle or heterocycle
is optionally substituted with one or more Z.sup.1 groups; c)
(C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups; d)
--X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more Z.sup.3 groups and optionally
substituted with one or more Z.sup.1 groups, and wherein any
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle is substituted with one or more
Z.sup.4 groups and optionally substituted with one or more Z.sup.1
groups; e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl
and --Xheterocycle, wherein any aryl heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups; f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups; and g)
--NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f, --OC(O)NR.sub.eR.sub.f,
--SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein each
(C.sub.1-C.sub.6)alkyl is optionally substituted with one or more
Z.sup.1 groups; R.sup.3a is (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl,
--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkyl-aryl,
--(C.sub.1-C.sub.6)alkyl-heterocycle,
--(C.sub.1-C.sub.6)alkyl-heteroaryl, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.2-C.sub.6)alkenyl,
--O(C.sub.2-C.sub.6)alkynyl, --O(C.sub.3-C.sub.7)cycloalkyl,
--Oaryl, --O(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl,
--O(C.sub.1-C.sub.6)alkyl-aryl,
--O(C.sub.1-C.sub.6)alkyl-heterocycle or
--O(C.sub.1-C.sub.6)alkyl-heteroaryl, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl of R.sup.3a,
either alone or as a group, is optionally substituted with one or
more groups selected from --O(C.sub.1-C.sub.6)alkyl, halo, oxo and
--CN, and wherein any (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle or heteroaryl of R.sup.3a, either alone or as a group,
is optionally substituted with one or more groups selected from
(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl, halo, oxo and
--CN; and R.sup.3a' is H; R.sup.3b is --(C.sub.7-C.sub.14)alkyl,
(C.sub.3-C.sub.7)carbocycle, aryl, heteroaryl, heterocycle,
--(C.sub.1-C.sub.6)alkylOH,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.2-C.sub.6)alkyl-O--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a
R.sub.b, --(C.sub.1-C.sub.6)alkylOC(O)--NR.sub.cR.sub.d,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--C(O)--OR.sub.b,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--C(O)--NR.sub.aR.sub.b,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.cR.sub.d,
--(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2Oaryl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)alkenyl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)alkynyl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.3-C.sub.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.3-C.sub.7)carbocyc-
le, --(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-aryl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-heteroaryl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-heterocycle,
--O(C.sub.7-C.sub.14)alkyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.aR.sub.b,
--O(C.sub.1-C.sub.6)alkylOC(O)--NR.sub.cR.sub.d,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--C(O)--OR.sub.b,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--C(O)--NR.sub.aR.sub.b,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)alkenyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.3-C.sub.7)carbocycle-
,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.3-C.sub.7)carboc-
ycle, --O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-aryl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-heteroaryl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-heterocycle,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--NR.sub.aR.sub.b,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.3-C.sub.7)carbocycle-
,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.3-C.sub.7)carboc-
ycle, --O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-aryl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2NR.sub.eR.sub.a,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.1-C.sub.6)allyl-NR.sub.aSO.sub.2Oaryl, -Oheteroaryl,
--Oheterocycle, --Sheteroaryl, --Sheterocycle, --S(O)heteroaryl,
--S(O)heterocycle, --SO.sub.2heteroaryl or --SO.sub.2heterocycle,
wherein any (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
--(C.sub.7-C.sub.14)alkyl, (C.sub.2-C.sub.6)alkynyl, aryl,
(C.sub.3-C.sub.7)carbocycle, heteroaryl or heterocycle of R.sup.3b,
either alone or as a group, is optionally substituted with one or
more Z.sup.1 groups; and R.sup.3b' is H, (C.sub.1-C.sub.6)alkyl or
--O(C.sub.1-C.sub.6)alkyl; or R.sup.3b and R.sup.3b' together with
the carbon to which they are attached form a heterocycle or
(C.sub.3-C.sub.7)carbocycle which heterocycle or
(C.sub.3-C.sub.7)carbocycle of R.sup.3b and R.sup.3b' together with
the carbon to which they are attached is optionally substituted
with one or more Z.sup.1 groups; R.sup.4a is selected from aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle and
heteroaryl of R.sup.4a is optionally substituted with one or more
groups each independently selected from halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, --OH,
--O(C.sub.1-C.sub.6)alkyl, SH, --S(C.sub.1-C.sub.6)alkyl,
--NH(C.sub.1-C.sub.6)alkyl and --N((C.sub.1-C.sub.6)alkyl).sub.2,
wherein (C.sub.1-C.sub.6)alkyl is optionally substituted with
hydroxy, --O(C.sub.1-C.sub.6)alkyl, cyano and oxo; R.sup.4b is
selected from: a) (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl
and (C.sub.2-C.sub.6)alkynyl, wherein (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
optionally substituted with one or more Z.sup.1 groups; b)
(C.sub.3-C.sub.14)carbocycle, wherein (C.sub.3-C.sub.14)carbocycle
is optionally substituted with one or more Z.sup.1 groups, wherein
two Z.sup.1 groups together with the atom or atoms to which they
are attached optionally form a (C.sub.3-C.sub.7)carbocycle or
heterocycle; c) spiro-heterocycle and bridged-heterocycle, wherein
spiro-heterocycle and bridged-heterocycle are each optionally
substituted with one or more Z.sup.1 groups, and wherein two
Z.sup.1 groups together with the atom or atoms to which they are
attached optionally form a (C.sub.3-C.sub.7)carbocycle or
heterocycle; d) aryl, heteroaryl, spiro-heterocycle,
fused-heterocycle and bridged-heterocycle, wherein aryl,
heteroaryl, spiro-heterocycle, fused-heterocycle and
bridged-heterocycle are each independently substituted with one or
more Z.sup.7 groups and optionally substituted with one or more
Z.sup.1 groups; or R.sup.4 and R.sup.3 together with the atoms to
which they are attached form a macroheterocycle or a
macrocarbocycle wherein any macroheterocycle or macrocarbocycle of
R.sup.4 and R.sup.3 together with the atoms to which they are
attached may be optionally substituted with one or more Z.sup.1
groups; and R.sup.3' is H, (C.sub.1-C.sub.6)alkyl or
--O(C.sub.1-C.sub.6)alkyl; R.sup.5a is selected from: a) halo,
nitro and cyano; b) R.sup.11, --C(.dbd.O)--R.sup.11,
--C(.dbd.O)--O--R.sup.11, --O--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more
Z.sup.11 groups; and c) --N(R.sup.9)R.sup.10,
--C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10
(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10, and a
(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; R.sup.5b is selected from: a)
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkylS(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.6)car-
bocycle,
--(C.sub.1-C.sub.6)alkylSO.sub.2(C.sub.1-C.sub.6)alkyl-(C.sub.3-C-
.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, --(C.sub.3-C.sub.7)halocarbocycle,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl, either alone or as part of a group, is
optionally substituted with one or more Z.sup.1 groups; b)
spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle is
optionally substituted with one or more Z.sup.1 groups, wherein two
Z.sup.1 groups together with the atom or atoms to which they are
attached optionally form a (C.sub.3-C.sub.7)carbocycle or
heterocycle, wherein the (C.sub.3-C.sub.7)carbocycle or heterocycle
is optionally substituted with one or more Z.sup.1 groups; c)
(C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups; d)
--X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any X(C.sub.1-C.sub.6)alkyl
and --X(C.sub.1-C.sub.6)haloalkyl is substituted with one or more
Z.sup.3 groups and optionally substituted with one or more Z.sup.1
groups, and wherein any --X(C.sub.2-C.sub.6)alkenyl,
--X(C.sub.2-C.sub.6)alkynyl and --X(C.sub.3-C.sub.7)carbocycle is
independently substituted with one or more Z.sup.4 groups and
optionally substituted with one or more Z.sup.1 groups; e) aryl,
heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and --Xheterocycle,
wherein any aryl, heteroaryl and heterocycle, either alone or as
part of a group are each independently substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups; f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more Z.sup.6 groups and
optionally substituted with one or more Z.sup.1 groups; and g)
--NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f, --OC(O)NR.sub.eR.sub.f,
--SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein any
(C.sub.1-C.sub.6)alkyl, as part of a group, is optionally
substituted with one or more Z.sup.1 groups; R.sup.6a is selected
from: a) H, halo, (C.sub.1-C.sub.6)alkyl, and
(C.sub.1-C.sub.6)haloalkyl; b) (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)cycloalkyl, nitro,
cyano, aryl, heterocycle and heteroaryl; c) --C(.dbd.O)--R.sup.11,
--C(.dbd.O)--O--R.sup.11, --O--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and d) --N(R.sup.9)R.sup.10,
--C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and wherein any aryl, heterocycle or
heteroaryl of R.sup.6a is optionally substituted with one or more
Z.sup.10 groups; R.sup.6b is selected from: a)
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
-halo(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle and heteroaryl, either
alone or as part of a group, is optionally substituted with one or
more Z.sup.1 groups; b) spiro-bicyclic carbocycle, fused-bicyclic
carbocycle and bridged-bicyclic carbocycle, wherein any
spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle is optionally substituted with one or
more Z.sup.1 groups, wherein two Z.sup.1 groups together with the
atom or atoms to which they are attached optionally form a
carbocycle or heterocycle wherein the carbocycle or heterocycle is
optionally substituted with one or more Z.sup.1 groups; c)
(C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups; d)
--X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl and --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more Z.sup.3 groups and optionally
substituted with one or more Z.sup.1 groups, and wherein any
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle is substituted with one or more
Z.sup.4 groups and optionally substituted with one or more Z.sup.1
groups; e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl
and --Xheterocycle, wherein any aryl, heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
Z
.sup.5 groups and optionally substituted with one or more Z.sup.1
groups; f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more Z.sup.6 groups and
optionally substituted with one or more Z.sup.1 groups; and g)
--NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f, --OC(O)NR.sub.eR.sub.f,
--SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f wherein any
(C.sub.1-C.sub.6)alkyl, as part of a group, is optionally
substituted with one or more Z.sup.1 groups; R.sup.7a is selected
from: a) H, halo, (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl; b) (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)cycloalkyl, nitro,
cyano, aryl, heterocycle and heteroaryl; c) --C(.dbd.O)--R.sup.11,
--C(.dbd.O)--O--R.sup.11, --O--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and d) --N(R.sup.9)R.sup.10,
--C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and wherein any aryl, heterocycle or
heteroaryl of R.sup.7a is optionally substituted with one or more
Z.sup.10 groups; R.sup.7b is selected from: a)
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbocy-
cle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)c-
arbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3--
C.sub.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.-
7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.3-C.sub.7)halocarbocycle,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl, either alone or as part of a group, is
optionally substituted with one or more Z.sup.1 groups; b)
spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle is
optionally substituted with one or more Z.sup.1 groups, wherein two
Z.sup.1 groups together with the atom or atoms to which they are
attached optionally form a (C.sub.3-C.sub.7)carbocycle or
heterocycle, wherein the (C.sub.3-C.sub.7)carbocycle or heterocycle
is optionally substituted with one or more Z.sup.1 groups; c)
(C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups; d)
--X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl and --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more Z.sup.3 groups and optionally
substituted with one or more Z.sup.1 groups, and wherein any
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle is substituted with one or more
Z.sup.4 groups and optionally substituted with one or more Z.sup.1
groups; e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl
and --Xheterocycle, wherein any aryl, heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups; f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups; and g)
--NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f, --OC(O)NR.sub.eR.sub.f,
--SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein each
(C.sub.1-C.sub.6)alkyl is optionally substituted with one or more
Z.sup.1 groups; R.sup.8a is selected from: a) halo, nitro and
cyano; b) R.sup.11, --C(.dbd.O)--R.sup.11,
--C(.dbd.O)--O--R.sup.11, --O--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more
Z.sup.11 groups; and c) --N(R.sup.9)R.sup.10,
--C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more
Z.sup.11 groups; R.sup.8b is selected from: a)
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
-halo(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle and heteroaryl, either
alone or as part of a group, is optionally substituted with one or
more Z.sup.1 groups; b) spiro-bicyclic carbocycle, fused-bicyclic
carbocycle and bridged-bicyclic carbocycle, wherein any
spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle is optionally substituted with one or
more Z.sup.1 groups, wherein two Z.sup.1 groups together with the
atom or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle wherein the
(C.sub.3-C.sub.7)carbocycle or heterocycle is optionally
substituted with one or more Z.sup.1 groups; c)
(C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups; d)
--X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl and --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more Z.sup.3 groups and optionally
substituted with one or more Z.sup.1 groups, and wherein any
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle is substituted with one or more
Z.sup.4 groups and optionally substituted with one or more Z.sup.1
groups; e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl
and --Xheterocycle, wherein any aryl, heteroaryl and heterocycle,
either alone or as part of a group is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups; f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more Z.sup.6 groups and
optionally substituted with one or more Z.sup.1 groups; and g)
--NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f, --OC(O)NR.sub.eR.sub.f,
--SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein each
(C.sub.1-C.sub.6)alkyl is optionally substituted with one or more
Z.sup.1 groups; R.sup.13a is selected from: a) R.sup.11,
--C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11, --O--R.sup.11,
--S--R.sup.11, --S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more
Z.sup.11 groups; and b) --C(.dbd.O)--N(R.sup.9)R.sup.10,
--SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkylaryl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, heterocycle and heteroaryl,
wherein aryl, heterocycle and heteroaryl are each optionally
substituted with one or more Z.sup.11 groups; R.sup.13b is selected
from: a)
--(C.sub.1-C.sub.6)allyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6
)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
-halo(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1,
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl, wherein any (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl, either alone or as part of a group, is
optionally substituted with one or more Z.sup.1 groups; b)
spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle are
optionally substituted with one or more Z.sup.1 groups, wherein two
Z.sup.1 groups together with the atom or atoms to which they are
attached optionally form a (C.sub.3-C.sub.7)carbocycle or
heterocycle wherein the (C.sub.3-C.sub.7)carbocycle or heterocycle
is optionally substituted with one or more Z.sup.1 groups; c)
(C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups; d)
--X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any X(C.sub.1-C.sub.6)alkyl
and --X(C.sub.1-C.sub.6)haloalkyl is substituted with one or more
Z.sup.3 groups and optionally substituted with one or more Z.sup.1
groups, and wherein any --X(C.sub.2-C.sub.6)alkenyl,
--X(C.sub.2-C.sub.6)alkynyl and --X(C.sub.3-C.sub.7)carbocycle, is
substituted with one or more Z.sup.4 groups and optionally
substituted with one or more Z.sup.1 groups; e) aryl, heteroaryl,
heterocycle, --Xaryl, --Xheteroaryl and --Xheterocycle, wherein any
aryl, heteroaryl and heterocycle, either alone or as part of a
group, is substituted with one or more Z.sup.5 groups and
optionally substituted with one or more Z.sup.1 groups; f)
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more Z.sup.6 groups and
optionally substituted with one or more Z.sup.1 groups; and g)
--C(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein each
(C.sub.1-C.sub.6)alkyl is optionally substituted with one or more
Z.sup.1 groups; or any of R.sup.5a and R.sup.6a, R.sup.6a and
R.sup.7a, R.sup.7a and R.sup.8a, R.sup.1 and R.sup.2 or R.sup.1 and
R.sup.13 together with the atoms to which they are attached form a
5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle,
wherein the 5 or 6-membered carbocycle or the 4, 5, 6 or 7-membered
heterocycle is optionally substituted with one or more substituents
each independently selected from halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)cycloalkyl, --OH, --O(C.sub.1-C.sub.6)alkyl, --SH,
--S(C.sub.1-C.sub.6)alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl
and --N((C.sub.1-C.sub.6)alkyl).sub.2; or any of R.sup.5 and
R.sup.6, R.sup.6 and R.sup.7 or R.sup.7 and R.sup.8, together with
the atoms to which they are attached form a 5 or 6-membered
carbocycle or a 4, 5, 6 or 7-membered heterocycle, wherein the 5 or
6-membered carbocycle or the 4, 5, 6 or 7-membered heterocycle are
each independently substituted with one or more Z.sup.7 or Z.sup.8
groups, wherein when two Z.sup.7 groups are on same atom the two
Z.sup.7 groups together with the atom to which they are attached
optionally form a (C.sub.3-C.sub.7)carbocycle or 4, 5 or 6-membered
heterocycle; or any of R.sup.1 and R.sup.8, R.sup.1 and R.sup.2 or
R.sup.1 and R.sup.13 together with the atoms to which they are
attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or
7-membered heterocycle, wherein the 5 or 6-membered carbocycle or
the 4, 5, 6 or 7-membered heterocycle are each independently
substituted with one or more Z.sup.7 or Z.sup.8 groups; wherein
when two Z.sup.7 groups are on same atom the two Z.sup.7 groups
together with the atom to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or 4, 5 or 6-membered heterocycle; X is
independently selected from O, --C(O)--, --C(O)O--, --S--,
--S(O)--, --SO.sub.2--, --(C.sub.1-C.sub.6)alkylO--,
--(C.sub.1-C.sub.6)alkylC(O)--, --(C.sub.1-C.sub.6)alkylC(O)O--,
--(C.sub.1-C.sub.6)alkylS--, --(C.sub.1-C.sub.6)alkylS(O)-- and
--(C.sub.1-C.sub.6)alkylSO.sub.2--; each Z.sup.1 is independently
selected from halo, --NO.sub.2, --OH, .dbd.NOR.sub.a, --SH, --CN,
--(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, --(C.sub.3-C.sub.7)halocarbocycle,
-aryl, -heteroaryl, -heterocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.2-C.sub.6)alkenyl, --O(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --Oaryl, -Oheteroaryl,
--Oheterocycle, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.2-C.sub.6)alkenyl, --S(C.sub.2-C.sub.6)alkynyl,
--S(C.sub.1-C.sub.6)haloalkyl, --S(C.sub.3-C.sub.7)carbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle, --Saryl, --Sheteroaryl,
--Sheterocycle, --S(O)(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.2-C.sub.6)alkenyl, --S(O)(C.sub.2-C.sub.6)alkynyl,
--S(O)(C.sub.1-C.sub.6)haloalkyl, --S(O)
(C.sub.3-C.sub.7)carbocycle, --S(O)(C.sub.3-C.sub.7)halocarbocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl, --S(O)aryl, --S(O)carbocycle,
--S(O)heteroaryl, --S(O)heterocycle,
--SO.sub.2(C.sub.2-C.sub.6)alkenyl,
--SO.sub.2(C.sub.2-C.sub.6)alkynyl,
--SO.sub.2(C.sub.1-C.sub.6)haloalkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.aC(O)R.sub.a,
--NR.sub.aC(O)OR.sub.a,
--NR.sub.aC(O)NR.sub.cR.sub.d--NR.sub.aSO.sub.2R.sub.b,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --OS(O).sub.2R.sub.a, --C(O)R.sub.a,
--C(O)OR.sub.b, --C(O)NR.sub.cR.sub.d, and --OC(O)NR.sub.cR.sub.d,
wherein any (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
--(C.sub.3-C.sub.7)halocarbocycle, (C.sub.3-C.sub.7)carbocycle,
(C.sub.3-C.sub.7)halocarbocycle, aryl, heteroaryl and heterocycle
of Z.sup.1, either alone or as part of a group, is optionally
substituted with one or more halogen, --OH, --OR.sub.b, --CN,
--NR.sub.aC(O).sub.2R.sub.b, heteroaryl, heterocycle,
--Oheteroaryl, --Oheterocycle, --NHheteroaryl, --NHheterocycle, or
--S(O).sub.2NR.sub.cR.sub.d; each Z.sup.2 is independently selected
from --NO.sub.2, --CN, Spiro-heterocycle, bridged-heterocycle,
spiro-bicyclic carbocycle, bridged-bicyclic carbocycle,
NR.sub.aSO.sub.2(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2aryl, --NR.sub.aSO.sub.2heteroaryl,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl; each Z.sup.3 is independently selected
from --NO.sub.2, --CN, --OH, oxo, .dbd.NOR.sub.a, thioxo, -aryl,
-heterocycle, -heteroaryl, (C.sub.3-C.sub.7)carbocycle,
--(C.sub.3-C.sub.7)halocarbocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.3-C.sub.7)carbocycle, --Ohalo(C.sub.3-C.sub.7)carbocycle,
--Oaryl, --Oheterocycle, --Oheteroaryl, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --S(C.sub.3-C.sub.7)halocarbocycle,
--Saryl, --Sheterocycle, --Sheteroaryl,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle, --S(O)aryl,
--S(O)heterocycle, --S(O)heteroaryl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, SO.sub.2aryl,
--SO.sub.2heterocycle, --SO.sub.2heteroaryl, --NR.sub.aR.sub.b,
--NR.sub.aC(O)R.sub.b, --C(O)NR.sub.cR.sub.d,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl; each Z.sup.4 is independently selected
from halogen, --(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.7)carbocycle, -halo(C.sub.1-C.sub.6)alkyl,
--NO.sub.2, --CN, --OH, oxo, .dbd.NOR.sub.a, thioxo, aryl,
heterocycle, heteroaryl, (C.sub.3-C.sub.7)halocarbocycle,
--O(C.sub.1-C.sub.6)alkyl, --O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --Oaryl, --Oheterocycle,
-Oheteroaryl, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --S(C.sub.3-C.sub.7)halocarbocycle,
-Saryl, --Sheterocycle, --Sheteroaryl,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle, --S(O)aryl,
--S(O)heterocycle, --S(O)heteroaryl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, SO.sub.2aryl,
--SO.sub.2heterocycle, --SO.sub.2heteroaryl, --NR.sub.aR.sub.b,
--NR.sub.aC(O)R.sub.a, --C(O)NR.sub.cR.sub.d,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.aSO.sub.2NR.sub.aR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl; each Z.sup.5 is independently selected
from --NO.sub.2, --CN, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --NR.sub.aSO.sub.2(C.sub.1-C.sub.6)alkyl,
--NR.sub.aSO.sub.2(C.sub.2-C.sub.6)alkenyl,
--NR.sub.aSO.sub.2(C.sub.2-C.sub.6)alkynyl,
--NR.sub.aSO.sub.2(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2aryl, --NR.sub.aSO.sub.2heteroaryl,
--NR.sub.aSO.sub.2heteroaryl, --NR.sub.aSO.sub.2heterocycle,
--NR.sub.aC(O)alkyl, --NR.sub.aC(O)alkenyl, --NR.sub.aC(O)alkynyl,
--NR.sub.aC(O) (C.sub.3-C.sub.7)carbocycle,
--NR.sub.aC(O)(C.sub.3-C.sub.7)halocarbocycle, --NR.sub.aC(O)aryl,
--NR.sub.aC(O)heteroaryl, --NR.sub.aC(O)heterocycle,
NR.sub.aC(O)NR.sub.eR.sub.d and NR.sub.aC(O)OR.sub.b; each Z.sup.6
is independently selected from --NO.sub.2, --CN, --NR.sub.aR.sub.a,
NR.sub.aC(O)R.sub.b, --C(O)NR.sub.cR.sub.d,
--(C.sub.3-C.sub.7)halocarbocycle, aryl, heteroaryl, heterocycle,
--Oaryl, --Oheteroaryl, --Oheterocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl,
--O(C.sub.3-C.sub.7)carbocycle, --Ohalo(C.sub.1-C.sub.6)alkyl,
--Saryl, --Sheteroaryl, --Sheterocycle,
--S(C.sub.3-C.sub.7)halocarbocycle, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --S(C.sub.1-C.sub.6)haloalkyl,
--S(O)aryl, --S(O)heteroaryl, --S(O)heterocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)halo(C.sub.1-C.sub.6)alkyl, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2halo(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2aryl, --NR.sub.aSO.sub.2heteroaryl,
--NR.sub.aSO.sub.2heteroaryl, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl; each Z.sup.7 is independently selected
from --NO.sub.2, .dbd.NOR.sub.a, --CN,
--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.2-C.sub.6)alkenyl-Z.sup.12, --(C.sub.2-C.sub.6)alkenylOH,
--(C.sub.2-C.sub.6)alkynyl-Z.sup.12, --(C.sub.2-C.sub.6)alkynyl-OH,
--(C.sub.1-C.sub.6)haloalkyl-Z.sup.12,
--(C.sub.1-C.sub.6)haloalkylOH,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.12,
--(C.sub.3-C.sub.7)carbocycleOH, (C.sub.3-C.sub.7)halocarbocycle,
--(C.sub.1-C.sub.6)alkylNR.sub.cR.sub.d,
--(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, aryl, heteroaryl,
heterocycle, --O(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--O(C.sub.2-C.sub.6)alkenyl, --O(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --Oaryl,
--O(C.sub.1-C.sub.6)alkylNR.sub.cR.sub.d,
--O(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--O(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, --Oheteroaryl,
--Oheterocycle, --S(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--S(C.sub.2-C.sub.6)alkenyl, --S(C.sub.2-C.sub.6)alkynyl,
--S(C.sub.1-C.sub.6)haloalkyl, --S(C.sub.3-C.sub.7)carbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle,
--S(C.sub.1-C.sub.6)alkylNR.sub.cR.sub.d,
--S(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--S(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, --Saryl,
--Sheteroaryl, --Sheterocycle, --S(O)(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.2-C.sub.6)alkenyl, --S(O)(C.sub.2-C.sub.6)alkynyl,
--S(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.1-C.sub.6)alkylNR.sub.cR.sub.d,
--S(O)(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--S(O)(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, --S(O)aryl,
--S(O)heteroaryl, --S(O)heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.2-C.sub.6)alkenyl,
--SO.sub.2(C.sub.2-C.sub.6)alkynyl,
--SO.sub.2(C.sub.1-C.sub.6)haloalkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkylNR.sub.cR.sub.d,
--SO.sub.2(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--SO.sub.2(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.aC(O)OR.sub.b,
--NR.sub.aC(O)NR.sub.cR.sub.d--NR.sub.aSO.sub.2R.sub.b,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --OS(O).sub.2R.sub.a,
--C(O)NR.sub.cR.sub.d, and --OC(O)NR.sub.cR.sub.d, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.3-C.sub.7)halocarbocycle, aryl,
heteroaryl and heterocycle of Z.sup.7, either alone or as part of a
group, is optionally substituted with one or more halogen, --OH,
--OR.sub.b, --CN,
--NR.sub.aC(O).sub.2R.sub.b, heteroaryl, heterocycle,
--Oheteroaryl, --Oheterocycle, --NHheteroaryl, --NHheterocycle, or
--S(O).sub.2NR.sub.cR.sub.d; each Z.sup.8 is independently selected
from --NO.sub.2 and --CN; each Z.sup.9 is independently selected
from --(C.sub.1-C.sub.6)alkyl and --O(C.sub.1-C.sub.6)alkyl; each
Z.sup.10 is independently selected from: i) halo, oxo, thioxo,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.1-C.sub.6)alkyl-, --OH,
--O(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)haloalkyl, --SH,
--S(C.sub.1-C.sub.6)alkyl, --SO(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl, --NH.sub.2,
--NH(C.sub.1-C.sub.6)alkyl and --N((C.sub.1-C.sub.6)alkyl).sub.2;
ii) (C.sub.1-C.sub.6)alkyl optionally substituted with --OH,
--O--(C.sub.1-C.sub.6)haloalkyl, or --O--(C.sub.1-C.sub.6)alkyl;
and iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle
and heteroaryl is optionally substituted with halo,
(C.sub.1-C.sub.6)alkyl or COOH; each Z.sup.11 is independently
selected from Z.sup.19, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--NH(C.sub.1-C.sub.4)alkyl,
--C(.dbd.O)--N((C.sub.1-C.sub.4)alkyl).sub.2, --C(.dbd.O)-aryl,
--C(.dbd.O)-heterocycle and --C(.dbd.O)-heteroaryl; each Z.sup.12
is independently selected from --NO.sub.2, .dbd.NOR.sub.a, thioxo,
aryl, heterocycle, heteroaryl, (C.sub.3-C.sub.7)halocarbocycle,
(C.sub.3-C.sub.7)carbocycle, --O(C.sub.3-C.sub.7)carbocycle,
--Ohalo(C.sub.3-C.sub.7)carbocycle, --Oaryl, --Oheterocycle,
--Oheteroaryl, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --Shalo(C.sub.3-C.sub.7)carbocycle,
--Saryl, --Sheterocycle, --Sheteroaryl,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)halo(C.sub.3-C.sub.7)carbocycle, --S(O)aryl,
--S(O)heterocycle, --S(O)heteroaryl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, --SO.sub.2aryl,
--SO.sub.2heterocycle, --SO.sub.2heteroaryl, --NR.sub.aR.sub.a,
--NR.sub.aC(O)R.sub.b, --C(O)NR.sub.cR.sub.d,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl; each Z.sup.13 is independently selected
from --NO.sub.2, --OH, .dbd.NOR.sub.a, --SH, --CN,
--(C.sub.3-C.sub.7)halocarbocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.2-C.sub.6)alkenyl, --O(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --Oaryl, --Oheteroaryl,
--Oheterocycle, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.2-C.sub.6)alkenyl, --S(C.sub.2-C.sub.6)alkynyl,
--S(C.sub.1-C.sub.6)haloalkyl, --S(C.sub.3-C.sub.7)carbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle, --Saryl, --Sheteroaryl,
--Sheterocycle, --S(O)(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.2-C.sub.6)alkenyl, --S(O)(C.sub.2-C.sub.6)alkynyl,
--S(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle, --S(O)aryl,
--S(O)heteroaryl, --S(O)heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.2-C.sub.6)alkenyl,
--SO.sub.2(C.sub.2-C.sub.6)alkynyl,
--SO.sub.2(C.sub.1-C.sub.6)haloalkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.cR.sub.d,
--NR.sub.aC(O)R.sub.a, --NR.sub.aC(O)OR.sub.b,
--NR.sub.aC(O)NR.sub.cR.sub.d--NR.sub.aSO.sub.2R.sub.b,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --OS(O).sub.2R.sub.a, --C(O)R.sub.a,
--C(O)OR.sub.b, --C(O)NR.sub.cR.sub.d, and --OC(O)NR.sub.cR.sub.d,
wherein any (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.3-C.sub.7)halocarbocycle, aryl,
heteroaryl and heterocycle of Z.sup.13, either alone or as part of
a group, is optionally substituted with one or more halogen, --OH,
--OR.sub.b, --CN, --NR.sub.aC(O).sub.2R.sub.b, -heteroaryl,
-heterocycle, --Oheteroaryl, --Oheterocycle, --NHheteroaryl,
--NHheterocycle, or --S(O).sub.2NR.sub.cR.sub.d; each Z.sup.14 is
independently selected from --NO.sub.2, .dbd.NOR.sub.a, --CN,
--(C.sub.3-C.sub.7)halocarbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2Oaryl and --OS(O).sub.2R.sub.a, wherein any
--(C.sub.3-C.sub.7)halocarbocycle of Z.sup.14, either alone or as
part of a group, is optionally substituted with one or more
halogen, --OH, --OR.sub.b, --CN, --NR.sub.aC(O).sub.2R.sub.b,
-heteroaryl, -heterocycle, -Oheteroaryl, --Oheterocycle,
--NHheteroaryl, --NHheterocycle, or --S(O).sub.2NR.sub.cR.sub.d;
each R.sub.a is independently H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)carbocycle, heterocycle, aryl,
aryl(C.sub.1-C.sub.6)alkyl-, heteroaryl or
heteroaryl(C.sub.1-C.sub.6)alkyl-, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle, heterocycle,
aryl or heteroaryl of R.sub.a, either alone or as part of a group,
is optionally substituted by one or more halogen, OH and cyano;
each R.sub.b is independently (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)carbocycle, heterocycle, aryl,
aryl(C.sub.1-C.sub.6)alkyl-, heteroaryl or
heteroaryl(C.sub.1-C.sub.6)alkyl-, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle, heterocycle,
aryl or heteroaryl of R.sub.b, either alone or as part of a group,
is optionally substituted by one or more halogen, OH and cyano;
R.sub.c and R.sub.d are each independently selected from H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle, aryl,
aryl(C.sub.1-C.sub.6)alkyl-, heterocycle, heteroaryl and
heteroaryl(C.sub.1-C.sub.6)alkyl-, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle, heterocycle,
aryl and heteroaryl of R.sub.e or R.sub.d, either alone or as part
of a group, is optionally substituted by one or more halogen, OH
and cyano; or R.sub.c and R.sub.d together with the nitrogen to
which they are attached form a heterocycle, wherein any heterocycle
of R.sub.e and R.sub.d together with the nitrogen to which they are
attached is optionally substituted by one or more halogen, OH or
cyano; each R.sub.e is independently selected from --OR.sub.a,
(C.sub.1-C.sub.6)alkyl and (C.sub.3-C.sub.7)carbocycle, wherein
(C.sub.1-C.sub.6)alkyl and (C.sub.3-C.sub.7)carbocycle is
substituted by one or more Z.sup.6 and optionally substituted with
one or more Z.sup.1, (C.sub.2-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein any
(C.sub.2-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl and
(C.sub.2-C.sub.6)alkynyl is optionally substituted with one or more
Z.sup.1; and aryl, heterocycle and heteroaryl wherein aryl,
heterocycle and heteroaryl is substituted by one or more Z.sup.5;
each R.sub.f is independently selected from --R.sub.g, --OR.,
--(C.sub.1-C.sub.6)alkyl-Z.sup.6, --SO.sub.2R.sub.g, --C(O)R.sub.g,
C(O)OR.sub.g and --C(O)NR.sub.eR.sub.g; and each R.sub.g is
independently selected from H, --OR.sub.a, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl, wherein any (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl of R.sub.g is optionally substituted
with one or more Z.sub.1 groups; or a salt thereof.
2. The compound of claim 1 wherein R.sup.3 is
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl or
--O(C.sub.1-C.sub.6)alkyl, wherein any (C.sub.1-C.sub.6)alkyl or
(C.sub.2-C.sub.6)alkenyl of R.sup.3 is optionally substituted with
one or more groups selected from --O(C.sub.1-C.sub.6)alkyl, halo,
oxo and CN, and wherein R.sup.3' is H.
3. The compound of claim 1 wherein R.sup.3 is
--O(C.sub.1-C.sub.6)alkyl, and wherein R.sup.3' is H.
4. The compound of claim 1 wherein R.sup.2 is halo, H or
--CH.sub.3.
5. The compound of claim 1 which is a compound of formula Ih
##STR00253## or a salt thereof.
6. The compound of claim 1 wherein R.sup.1 is H.
7. The compound of claim 1 wherein R.sup.6 is H.
8. The compound of claim 1 wherein R.sup.5 is H or
(C.sub.1-C.sub.6)alkyl.
9. The compound of claim 1 which is a compound of formula Ik
##STR00254## or a salt thereof.
10. The compound of claim 1 wherein R.sup.4 is selected from: a)
aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and
heteroaryl is optionally substituted with one or more groups each
independently selected from halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)cycloalkyl, --OH, --O(C.sub.1-C.sub.6)alkyl, --SH,
--S(C.sub.1-C.sub.6)alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl
and --N((C.sub.1-C.sub.6)alkyl).sub.2, wherein
(C.sub.1-C.sub.6)alkyl is optionally substituted with hydroxy,
--O(C.sub.1-C.sub.6)alkyl, cyano or oxo; b)
(C.sub.3-C.sub.14)carbocycle, wherein (C.sub.3-C.sub.14)carbocycle
is optionally substituted with one or more Z.sup.1 groups, wherein
two Z.sup.1 groups together with the atom or atoms to which they
are attached optionally form a (C.sub.3-C.sub.7)carbocycle or
heterocycle; and c) aryl, heteroaryl, spiro-heterocycle,
fused-heterocycle and bridged-heterocycle, wherein aryl,
heteroaryl, spiro-heterocycle, fused-heterocycle and
bridged-heterocycle are each independently substituted with one or
more Z.sup.7 groups and optionally substituted with one or more
Z.sup.1 groups.
11. The compound of claim 1 wherein R.sup.4 is selected from: a)
aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and
heteroaryl is optionally substituted with one or more groups each
independently selected from halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)cycloalkyl, --OH, --O(C.sub.1-C.sub.6)alkyl, --SH,
--S(C.sub.1-C.sub.6)alkyl, --NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)alkyl).sub.2, wherein (C.sub.1-C.sub.6)alkyl
is optionally substituted with hydroxy, --O(C.sub.1-C.sub.6)alkyl,
cyano or oxo; and b) aryl, heteroaryl and fused-heterocycle,
wherein aryl, heteroaryl and fused-heterocycle are each
independently substituted with one or more Z.sup.7 groups and
optionally substituted with one or more Z.sup.1 groups.
12. The compound of claim 1 wherein R.sup.4 is selected from: a)
heterocycle, wherein heterocycle is optionally substituted with one
or more groups each independently selected from halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, --OH,
--O(C.sub.1-C.sub.6)allyl, --SH, --S(C.sub.1-C.sub.6)allyl,
--NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)alkyl).sub.2, wherein (C.sub.1-C.sub.6)alkyl
is optionally substituted with hydroxy, --O(C.sub.1-C.sub.6)alkyl,
cyano or oxo; and b) fused-heterocycle, wherein fused-heterocycle
is substituted with one or more Z.sup.7 groups and optionally
substituted with one or more Z.sup.1 groups.
13. The compound of claim 1 wherein R.sup.4 is: ##STR00255##
14. The compound of claim 1 wherein R.sup.4 is: ##STR00256##
15. The compound of claim 1 wherein R.sup.7 is selected from: a) H,
halo, (C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)haloalkyl; b)
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, nitro, cyano, aryl, heterocycle and
heteroaryl, wherein any aryl, heterocycle or heteroaryl is
optionally substituted with one or more Z.sup.10 groups; c)
--C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11, --O--R.sup.11,
--S--R.sup.11, --S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups; d) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10
(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --SO.sub.2--R.sup.11,
--C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11 and
--C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups;
e)-(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 or
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle and heteroaryl, either
alone or as a group, is optionally substituted with one or more
Z.sup.1 groups; f) --X(C.sub.1-C.sub.6)alkyl,
X(C.sub.1-C.sub.6)haloalkyl, X(C.sub.2-C.sub.6)alkenyl,
--X(C.sub.2-C.sub.6)alkynyl and --X(C.sub.3-C.sub.7)carbocycle,
wherein any X(C.sub.1-C.sub.6)alkyl and X(C.sub.1-C.sub.6)haloalkyl
is substituted with one or more Z.sup.3 groups and optionally
substituted with one or more Z.sup.1 groups, and wherein any
X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle is substituted with one or more
Z.sup.4 groups and optionally substituted with one or more Z.sup.1
groups; g) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl
is substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups; h) aryl, heteroaryl,
heterocycle, --Xaryl, --Xheteroaryl and --Xheterocycle, wherein any
aryl, heteroaryl and heterocycle, either alone or as part of a
group, is substituted with one or more Z.sup.5 groups and
optionally substituted with one or more Z.sup.1 groups; i)
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups; and j)
--NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f, --OC(O)NR.sub.eR.sub.f,
--SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein each
(C.sub.1-C.sub.6)alkyl is optionally substituted with one or more
Z.sup.1 groups.
16. The compound of claim 1 wherein R.sup.7 is selected from: a) H,
(C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)haloalkyl; b)
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, heterocycle and heteroaryl,
wherein any aryl, heterocycle or heteroaryl is optionally
substituted with one or more Z.sup.10 groups; c) --C(.dbd.O)--
--O--R.sup.11, --O--R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups; d) --N(R.sup.9)R.sup.10, C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10, wherein each R.sup.9
is independently selected from H, (C.sub.1-C.sub.6)alkyl and
(C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkonyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups; e) --(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle
and --(C.sub.2-C.sub.6)alkynyl-aryl, wherein any
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle and
--(C.sub.2-C.sub.6)alkynyl-aryl is optionally substituted with one
or more Z.sup.1 groups; f) --X(C.sub.1-C.sub.6)alkyl, wherein
--X(C.sub.1-C.sub.6)alkyl is substituted with one or more Z.sup.3
groups and optionally substituted with one or more Z.sup.1 groups,
and wherein X is O; g) (C.sub.1-C.sub.6)alkyl, wherein
(C.sub.1-C.sub.6)alkyl is substituted with one or more Z.sup.2
groups and optionally substituted with one or more Z.sup.1 groups;
h) aryl, heteroaryl and heterocycle, wherein any aryl, heteroaryl
and heterocycle is substituted with one or more Z.sup.5 groups and
optionally substituted with one or more Z.sup.1 groups; i)
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein any
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl is
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups; and j)
--NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f, wherein
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f is optionally substituted
with one or more Z.sup.1 groups.
17. The compound of claim 1 wherein R.sup.7 is selected from: a) H,
(C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)haloalkyl; b)
(C.sub.2-C.sub.6)alkynyl and aryl, wherein aryl is optionally
substituted with one or more Z.sup.10 groups; c)
(C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups; d) aryl, wherein aryl
is substituted with one or more Z.sup.5 groups and optionally
substituted with one or more Z.sup.1 groups; and e)
(C.sub.1-C.sub.6)haloalkyl, wherein (C.sub.1-C.sub.6)haloalkyl is
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z1 groups.
18. The compound of claim 1 wherein R.sup.7 is selected from: a)
(C.sub.1-C.sub.6)haloalkyl; and b) (C.sub.1-C.sub.6)haloalkyl,
wherein (C.sub.1-C.sub.6)haloalkyl is substituted with one or more
Z.sup.6 groups and optionally substituted with one or more Z.sup.1
groups.
19. The compound of claim 1 wherein R.sup.7 is: ##STR00257##
##STR00258## ##STR00259##
20. The compound of claim 1 selected from: ##STR00260##
##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265##
##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270##
##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275##
##STR00276## ##STR00277## ##STR00278## ##STR00279## ##STR00280##
##STR00281## ##STR00282## and salts thereof.
21. A pharmaceutical composition comprising a compound of formula I
as described in claim 1, or a pharmaceutically acceptable salt
thereof, in combination with a pharmaceutically acceptable
carrier.
22. A method of treating the proliferation of the HIV virus,
treating AIDS or delaying the onset of AIDS or ARC symptoms in a
mammal comprising administering a compound of formula I as
described in claim 1, or a pharmaceutically acceptable salt
thereof, to the mammal.
23-25. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This patent application claims the benefit of priority of
U.S. application Ser. No. 61/361,335, filed Jul. 2, 2010.
BACKGROUND OF THE INVENTION
[0002] Human immunodeficiency virus (HIV) infection and related
diseases are a major public health problem worldwide. Human
immunodeficiency virus type 1 (HW-1) encodes three enzymes which
are required for viral replication: reverse transcriptase,
protease, and integrase. Although drugs targeting reverse
transcriptase and protease are in wide use and have shown
effectiveness, particularly when employed in combination, toxicity
and development of resistant strains have limited their usefulness
(Palella, et al N. Engl. J. Med. (1998) 338:853-860; Richman, D. D.
Nature (2001) 410:995-1001). Accordingly, there is a need for new
agents that inhibit the replication of HIV. There is also a need
for agents that are directed against alternate sites in the viral
life cycle including agents that target the interaction of Lens
Epithelial Derived Growth Factor (LEDGF/p75) and HIV-1
integrase.
SUMMARY OF THE INVENTION
[0003] In one embodiment, the invention provides a compound of the
invention which is a compound of formula I:
##STR00002##
wherein:
[0004] G.sup.1 is N, G.sup.2 is CR.sup.8, and the dashed bond is a
double bond; or
[0005] G.sup.1 is CR.sup.5, G.sup.2 is N, and the dashed bond is a
double bond; or
[0006] G.sup.1 is CR.sup.5, G.sup.2 is NR.sup.13, the dashed bond
is a single bond, and R.sup.7 is an oxo (.dbd.O) group; or
[0007] G.sup.1 is CR.sup.5, G.sup.2 is NR.sup.13, the dashed bond
is a single bond, and R.sup.7 and R.sup.13 together with the atoms
to which they are attached form a heteroaryl, wherein the
heteroaryl is optionally substituted with one or more (e.g. 1, 2,
3, 4 or 5) Z.sup.1 groups;
[0008] R.sup.1 is R.sup.1a or R.sup.1b;
[0009] R.sup.2 is R.sup.2a or R.sup.2b;
[0010] R.sup.3 is R.sup.3a or R.sup.3b;
[0011] R.sup.3' is R.sup.3a' or R.sup.3b';
[0012] R.sup.4 is R.sup.4a or R.sup.4b;
[0013] R.sup.5 is R.sup.5a or R.sup.5b;
[0014] R.sup.6 is R.sup.6a or R.sup.6b;
[0015] R.sup.7 is R.sup.7a or R.sup.7b;
[0016] R.sup.8 is R.sup.8a or R.sup.8b;
[0017] R.sup.13 is R.sup.13a or R.sup.13b;
[0018] R.sup.1a is selected from:
[0019] a) H, halo, (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0020] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, nitro, cyano, aryl, heterocycle and
heteroaryl;
[0021] c) --C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11,
--O--R.sup.n, --S--R.sup.n, --S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.n and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and [0022] d) --N(R.sup.9)R.sup.10,
--C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.n, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl,
[0023] and wherein any aryl, heterocycle or heteroaryl of R.sup.1a
is optionally substituted with one or more (e.g. 1, 2 or 3)
Z.sup.10 groups;
[0024] R.sup.1b is selected from:
[0025] a)
--(C.sub.1-C.sub.6)allyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.-
7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)allyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)allyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)allyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.3-C.sub.7)halocarbocycle,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl, either alone or as part of a group, is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0026] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle is
optionally substituted with one or more Z.sup.1 groups (e.g. 1, 2,
3, 4 or 5), wherein two Z.sup.1 groups together with the atom or
atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle, wherein the
(C.sub.3-C.sub.7)carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0027] c) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.2 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0028] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl and --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.3 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, and wherein any X(C.sub.2-C.sub.6)alkenyl,
--X(C.sub.2-C.sub.6)alkynyl and --X(C.sub.3-C.sub.7)carbocycle is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0029] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle, wherein any aryl heteroaryl and heterocycle, either
alone or as part of a group, is substituted with one or more (e.g.
1, 2, 3, 4 or 5) Z.sup.5 groups and optionally substituted with one
or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0030] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.6 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; and
[0031] g) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f wherein any
(C.sub.1-C.sub.6)alkyl, as a part of group, is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0032] R.sup.2a is selected from:
[0033] a) H, (C.sub.1-C.sub.6)alkyl and
--O(C.sub.1-C.sub.6)alkyl;
[0034] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle, heteroaryl, halo, nitro and cyano;
[0035] c) C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11,
--S--R.sup.11, --S(O)--R.sup.11, --SO.sub.2--.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl and
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups; and
[0036] d) --OH, --O(C.sub.2-C.sub.6)alkenyl,
--O(C.sub.2-C.sub.6)alkynyl, --O(C.sub.1-C.sub.6)haloalkyl,
--O(C.sub.3-C.sub.7)cycloalkyl, --Oaryl, --Oheterocycle and
--Oheteroaryl;
[0037] e) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10, and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl;
[0038] R.sup.2b is selected from:
[0039] a)
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.-
7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)allyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)allyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
(C.sub.3-C.sub.7)halocarbocycle, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)halocarbocycle, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl, either alone or as part of a group, is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0040] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, and wherein two Z.sup.1 groups together with the
atom or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle, wherein the
(C.sub.3-C.sub.7)carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0041] c) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.2 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0042] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl and --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.3 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, and wherein any --X(C.sub.2-C.sub.6)alkenyl,
--X(C.sub.2-C.sub.6)alkynyl and --X(C.sub.3-C.sub.7)carbocycle is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0043] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle; wherein any aryl, heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
(e.g. 1, 2, 3, 4 or 5) Z.sup.5 groups and optionally substituted
with one or more Z.sup.1 groups;
[0044] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.6 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; and
[0045] g) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein any
(C.sub.1-C.sub.6)alkyl, as a part of group, is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0046] R.sup.3a is (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl,
--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkyl-aryl,
--(C.sub.1-C.sub.6)alkyl-heterocycle,
--(C.sub.1-C.sub.6)alkyl-heteroaryl, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.2-C.sub.6)alkenyl,
--O(C.sub.2-C.sub.6)alkynyl, --O(C.sub.3-C.sub.7)cycloalkyl,
--Oaryl, --O(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl,
--O(C.sub.1-C.sub.6)alkyl-aryl,
--O(C.sub.1-C.sub.6)alkyl-heterocycle or
--O(C.sub.1-C.sub.6)alkyl-heteroaryl, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl of R.sup.3a,
either alone or as part of a group, is optionally substituted with
one or more (e.g. 1, 2 or 3) groups selected from
--O(C.sub.1-C.sub.6)alkyl, halo, oxo and --CN, and wherein any
(C.sub.3-C.sub.7)cycloalkyl, aryl, heterocycle or heteroaryl of
R.sup.3a, either alone or as part of a group, is optionally
substituted with one or more groups selected from
(C.sub.1-C.sub.6)allyl, --O(C.sub.1-C.sub.6)alkyl, halo, oxo and
--CN; and R.sup.3a' is H;
[0047] R.sup.3b is --(C.sub.7-C.sub.14)alkyl,
(C.sub.3-C.sub.7)carbocycle, aryl, heteroaryl, heterocycle,
--(C.sub.1-C.sub.6)alkylOH,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.2-C.sub.6)alkyl-O--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-NR.sub.aR.sub.b,
--(C.sub.1-C.sub.6)alkylOC(O)--NR.sub.cR.sub.d,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--C(O)--OR.sub.6,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--C(O)--NR.sub.aR.sub.b,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.cR.sub.d,
--(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2Oaryl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.1-C.sub.6)allyl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)alkenyl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)allynyl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.3-C.sub.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.3-C.sub.7)carbocyc-
le, --(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-aryl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-heteroaryl,
--(C.sub.1-C.sub.6)allyl-NR.sub.a--SO.sub.2-heterocycle,
--O(C.sub.7-C.sub.14)alkyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.aR.sub.b,
--O(C.sub.1-C.sub.6)alkylOC(O)--NR.sub.eR.sub.a,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--C(O)--OR.sub.b,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--C(O)--NR.sub.aR.sub.b,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)alkenyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.3-C.sub.7)carbocycle-
,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.3-C.sub.7)carboc-
ycle, --O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-aryl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-heteroaryl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-heterocycle,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--NR.sub.aR.sub.6,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.3-C.sub.7)carbocycle-
,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.3-C.sub.7)carboc-
ycle, --O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-aryl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2Oaryl, --Oheteroaryl,
--Oheterocycle, --Sheteroaryl, --Sheterocycle, --S(O)heteroaryl,
--S(O)heterocycle, --SO.sub.2heteroaryl or --SO.sub.2heterocycle,
wherein any (C.sub.1-C.sub.6)alkyl, --(C.sub.7-C.sub.14)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
(C.sub.3-C.sub.7)carbocycle, heteroaryl or heterocycle of R.sup.3b,
either alone or as part of a group, is optionally substituted with
one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups; and R.sup.3b' is
H, (C.sub.1-C.sub.6)alkyl or --O(C.sub.1-C.sub.6)alkyl; or R.sup.3b
and R.sup.3b' together with the carbon to which they are attached
form a heterocycle or (C.sub.3-C.sub.7)carbocycle which heterocycle
or (C.sub.3-C.sub.7)carbocycle of R.sup.3'' and R.sup.3b' together
with the carbon to which they are attached is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0048] R.sup.4a is selected from aryl, heterocycle and heteroaryl,
wherein any aryl, heterocycle and heteroaryl of R.sup.4a is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
groups each independently selected from halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, --OH,
--O(C.sub.1-C.sub.6)alkyl, --SH, --S(C.sub.1-C.sub.6)alkyl,
--NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)allyl).sub.2, wherein (C.sub.1-C.sub.6)alkyl
is optionally substituted with hydroxy, --O(C.sub.1-C.sub.6)alkyl,
cyano and oxo;
[0049] R.sup.4b is selected from;
[0050] a) (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl and
(C.sub.2-C.sub.6)alkynyl, wherein (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0051] b) (C.sub.3-C.sub.14)carbocycle, wherein
(C.sub.3-C.sub.14)carbocycle is optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups, wherein two Z.sup.1
groups together with the atom or atoms to which they are attached
optionally form a (C.sub.3-C.sub.7)carbocycle or heterocycle;
[0052] c) spiro-heterocycle and bridged-heterocycle, wherein
spiro-heterocycle and bridged-heterocycle are each optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups,
and wherein two Z.sup.1 groups together with the atom or atoms to
which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle; and
[0053] d) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle
and bridged-heterocycle, wherein aryl, heteroaryl,
spiro-heterocycle, fused-heterocycle and bridged-heterocycle are
each independently substituted with one or more (e.g. 1, 2, 3, 4 or
5) Z.sup.7 groups and optionally substituted with one or more (e.g.
1, 2, 3, 4 or 5) Z.sup.1 groups; or
[0054] R.sup.4 and R.sup.3 together with the atoms to which they
are attached form a macroheterocycle or a macrocarbocycle wherein
any macroheterocycle or macrocarbocycle of R.sup.4 and R.sup.3
together with the atoms to which they are attached may be
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; and R.sup.3' is H, (C.sub.1-C.sub.6)alkyl or
--O(C.sub.1-C.sub.6)alkyl;
[0055] R.sup.5a is selected from:
[0056] a) halo, nitro and cyano;
[0057] b) R.sup.11, --C(.dbd.O)--R.sup.11,
--C(.dbd.O)--O--R.sup.11, --O--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups; and
[0058] c) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10, and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.)OR.sup.11, --C(.dbd.O)OR.sup.11 and
--C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl;
[0059] R.sup.5b is selected from:
[0060] a)
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)allyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkylS(O)--(C.sub.1-C.sub.6)allyl-(C.sub.3-C.sub-
.6)carbocycle, --(C.sub.1-C.sub.6)alkylS
O.sub.2(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)halocarbocycle, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl, either alone or as part of a group, is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0061] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle, wherein the
(C.sub.3-C.sub.7)carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0062] c) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.2 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0063] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl and --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.3 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, and wherein any --X(C.sub.2-C.sub.6)alkenyl,
--X(C.sub.2-C.sub.6)alkynyl and --X(C.sub.3-C.sub.7)carbocycle is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0064] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle, wherein any aryl, heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
(e.g. 1, 2, 3, 4 or 5) Z.sup.5 groups and optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0065] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.6 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups; and
[0066] g) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein any
(C.sub.1-C.sub.6)alkyl, as part of a group, is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0067] R.sup.6a is selected from:
[0068] a) H, halo, (C.sub.1-C.sub.6)alkyl, and
(C.sub.1-C.sub.6)haloalkyl;
[0069] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, nitro, cyano, aryl, heterocycle and
heteroaryl;
[0070] c) --C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11,
--O--R.sup.11, --S--R.sup.11, --S(O)--R.sup.11,
--SO.sub.2--R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)allyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and
[0071] d) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.16,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and wherein any aryl, heterocycle or
heteroaryl of R.sup.6a is optionally substituted with one or more
(e.g. 1, 2 or 3) Z.sup.10 groups;
[0072] R.sup.6b is selected from:
[0073] a)
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.-
7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
halo(C.sub.3-C.sub.7)carbocycle, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle and heteroaryl, either
alone or as part of a group, is optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0074] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a carbocycle or
heterocycle wherein the carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0075] c) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.2 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0076] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl and --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.3 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, and wherein any --X(C.sub.2-C.sub.6)alkenyl,
--X(C.sub.2-C.sub.6)alkynyl and --X(C.sub.3-C.sub.7)carbocycle is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0077] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle, wherein any aryl, heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
(e.g. 1, 2, 3, 4 or 5) Z.sup.5 groups and optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0078] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.6 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z1 groups; and
[0079] g) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)allyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f wherein any
(C.sub.1-C.sub.6)alkyl, as part of a group, is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0080] R.sup.7a is selected from:
[0081] a) H, halo, (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0082] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, nitro, cyano, aryl, heterocycle and
heteroaryl;
[0083] c) --C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.n,
--O--R.sup.n, --S--R.sup.n, --S(O)--R.sup.n, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.n,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloallyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and
[0084] d) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)allyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.n, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl,
[0085] and wherein any aryl, heterocycle or heteroaryl of R.sup.7a
is optionally substituted with one or more (e.g. 1, 2 or 3)
Z.sup.10 groups;
[0086] R.sup.7b is selected from:
[0087] a)
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.-
13, --C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
C.sub.6)alkyl-Z.sup.13, --S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)halocarbocycle, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.3-C.sub.7)halocarbocycle,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl, either alone or as part of a group, is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0088] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle, wherein the
(C.sub.3-C.sub.7)carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0089] c) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.2 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0090] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl and --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.3 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, and wherein any X(C.sub.2-C.sub.6)alkenyl,
--X(C.sub.2-C.sub.6)alkynyl and --X(C.sub.3-C.sub.7)carbocycle is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0091] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle, wherein any aryl, heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
(e.g. 1, 2, 3, 4 or 5) Z.sup.5 groups and optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0092] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.6 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; and
[0093] g) --NR.sub.eR.sub.f, --C(O)Nlt.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NIZ.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)allyl-SO.sub.2NR.sub.eR.sub.f, wherein any
(C.sub.1-C.sub.6)alkyl, as a part of group, is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0094] R.sup.8a is selected from:
[0095] a) halo, nitro and cyano;
[0096] b) R.sup.11, --C(.dbd.O)--R.sup.11,
--C(.dbd.O)--O--R.sup.11, --O--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)allgl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups; and
[0097] c) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl--C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups;
[0098] R.sup.8b is selected from:
[0099] a)
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.-
13, --C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
C.sub.6)allyl-Z.sup.13, --S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)allyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)allyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)allyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
halo(C.sub.3-C.sub.7)carbocycle, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle and heteroaryl, either
alone or as part of a group, is optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0100] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein any Spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle wherein the
(C.sub.3-C.sub.7)carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0101] c) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)allyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.2 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0102] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl and --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.3 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, and wherein any X(C.sub.2-C.sub.6)alkenyl,
--X(C.sub.2-C.sub.6)alkynyl and --X(C.sub.3-C.sub.7)carbocycle is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0103] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle, wherein any aryl, heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
(e.g. 1, 2, 3, 4 or 5) Z.sup.5 groups and optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0104] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.6 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups; and
[0105] g) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NRA.sub.r, wherein any
(C.sub.1-C.sub.6)alkyl, as part of a group, is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0106] R.sup.13a is selected from:
[0107] a) R.sup.11, --C(.dbd.O)--R.sup.11,
--C(.dbd.O)--O--R.sup.11, --O--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups; and
[0108] b) --C(.dbd.O)--N(R.sup.9)R.sup.10,
--SO.sub.2--NR.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkylaryl, aryl, heterocycle and heteroaryl,
wherein aryl, heterocycle and heteroaryl are each optionally
substituted with one or more (e.g. 1, 2 or 3) Z.sup.11 groups;
[0109] R.sup.13b is selected from:
[0110] a)
--(C.sub.1-C.sub.6)allyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.-
13, --C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
-halo(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1,
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3,
--NR.sub.aSO.sub.2NR.sub.cR.sub.4,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl, wherein any (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl,
heterocycle and heteroaryl, either alone or as part of a group, is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0111] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle, wherein spiro-bicyclic carbocycle,
fused-bicyclic carbocycle and bridged-bicyclic carbocycle are
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle wherein the
(C.sub.3-C.sub.7)carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0112] c) (C.sub.1-C.sub.6)allyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.2 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0113] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl, is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.3 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups, and wherein any --X(C.sub.2-C.sub.6)alkenyl,
--X(C.sub.2-C.sub.6)alkynyl and --X(C.sub.3-C.sub.7)carbocycle, is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0114] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle, wherein any aryl, heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
(e.g. 1, 2, 3, 4 or 5) Z.sup.5 groups and optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0115] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.6 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups; and
[0116] g) --C(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein any
(C.sub.1-C.sub.6)alkyl, as part of a group, is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0117] or any of R.sup.5a and Rha, R.sup.6a and R.sup.7a, R.sup.7a
and R.sup.8a, and R.sup.8, R.sup.1 and R.sup.2 or R.sup.1 and
R.sup.13 together with the atoms to which they are attached form a
5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle,
wherein the 5 or 6-membered carbocycle or the 4, 5, 6 or 7-membered
heterocycle is optionally substituted with one or more (e.g. 1, 2
or 3) substituents each independently selected from halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, --OH,
--O(C.sub.1-C.sub.6)alkyl, --SH, --S(C.sub.1-C.sub.6)alkyl,
--NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)alk.sub.Y1).sub.2;
[0118] or any of R.sup.5 and R.sup.6, R.sup.6 and R.sup.7 or
R.sup.7 and R.sup.8, together with the atoms to which they are
attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or
7-membered heterocycle, wherein the 5 or 6-membered carbocycle or
the 4, 5, 6 or 7-membered heterocycle are each independently
substituted with one or more (e.g. 1, 2 or 3) Z.sup.7 or Z.sup.8
groups, wherein when two Z.sup.7 groups are on same atom the two
Z.sup.7 groups together with the atom to which they are attached
optionally form a (C.sub.3-C.sub.7)carbocycle or 4, 5 or 6-membered
heterocycle;
[0119] or any of Wand R.sup.8, R.sup.1 and R.sup.2 or Wand R.sup.13
together with the atoms to which they are attached form a 5 or
6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle,
wherein the 5 or 6-membered carbocycle or the 4, 5, 6 or 7-membered
heterocycle are each independently substituted with one or more
(e.g. 1, 2 or 3) Z.sup.7 or Z.sup.8 groups; wherein when two
Z.sup.7 groups are on same atom the two Z.sup.7 groups together
with the atom to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or 4, 5 or 6-membered heterocycle;
[0120] X is independently selected from O, --C(O)--, --C(O)O--,
--S--, --S(O)--, --SO.sub.2--, --(C.sub.1-C.sub.6)alkylO--,
--(C.sub.1-C.sub.6)alkylC(O)--, --(C.sub.1-C.sub.6)alkylC(O)O--,
--(C.sub.1-C.sub.6)alkylS--, --(C.sub.1-C.sub.6)alkylS(O)-- and
--(C.sub.1-C.sub.6)alkylSO.sub.2--;
[0121] each Z.sup.1 is independently selected from halo,
--NO.sub.2, --OH, .dbd.NOR.sub.a, --SH, --CN,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.3-C.sub.7)halocarbocycle, aryl,
heteroaryl, heterocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.2-C.sub.6)alkenyl, --O(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --Oaryl, --Oheteroaryl,
--Oheterocycle, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.2-C.sub.6)alkenyl, --S(C.sub.2-C.sub.6)alkynyl,
--S(C.sub.1-C.sub.6)haloalkyl, --S(C.sub.3-C.sub.7)carbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle, --Saryl, --Sheteroaryl,
--Sheterocycle, --S(O)(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.2-C.sub.6)alkenyl, --S(O)(C.sub.2-C.sub.6)alkynyl,
--S(O)(C.sub.1-C.sub.6)haloalkyl, --S(O)
(C.sub.3-C.sub.7)carbocycle, --S(O)(C.sub.3-C.sub.7)halocarbocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl, --S(O)aryl, --S(O)carbocycle,
--S(O)heteroaryl, --S(O)heterocycle,
--SO.sub.2(C.sub.2-C.sub.6)alkenyl,
--SO.sub.2(C.sub.2-C.sub.6)alkynyl,
--SO.sub.2(C.sub.1-C.sub.6)haloalkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.aC(O)R.sub.a,
--NR.sub.aC(O)OR.sub.a,
--NR.sub.aC(O)NR.sub.cR.sub.d--NR.sub.aSO.sub.2R.sub.b,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --OS(O).sub.2R.sub.a, --C(O)R.sub.a,
--C(O)OR.sub.b, --C(O)NR.sub.cR.sub.d, and --OC(O)NR.sub.cR.sub.d,
wherein any (C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)halocarbocycle, (C.sub.3-C.sub.7)carbocycle,
(C.sub.3-C.sub.7)halocarbocycle, aryl, heteroaryl and heterocycle
of Z, either alone or as part of a group, is optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) halogen, --OH, --OR.sub.b,
--CN, --NR.sub.aC(O).sub.2R.sub.b, -heteroaryl, -heterocycle,
--Oheteroaryl, --Oheterocycle, --NHheteroaryl, --NHheterocycle or
--S(O).sub.2NR.sub.cR.sub.d;
[0122] each Z.sup.2 is independently selected from --NO.sub.2,
--CN, spiro-heterocycle, bridged-heterocycle, spiro-bicyclic
carbocycle, bridged-bicyclic carbocycle,
NR.sub.aSO.sub.2(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2aryl, --NR.sub.aSO.sub.2heteroaryl,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl;
[0123] each Z.sup.3 is independently selected from --NO.sub.2,
--CN, --OH, oxo, .dbd.NOR.sub.a, thioxo, -aryl, -heterocycle,
-heteroaryl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.3-C.sub.7)halocarbocycle, --O(C.sub.3-C.sub.7)carbocycle,
--Ohalo(C.sub.3-C.sub.7)carbocycle, --Oaryl, --Oheterocycle,
Oheteroaryl, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --S(C.sub.3-C.sub.7)halocarbocycle,
--Saryl, --Sheterocycle, --Sheteroaryl,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle, --S(O)aryl,
--S(O)heterocycle, --S(O)heteroaryl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, SO.sub.2aryl,
--SO.sub.2heterocycle, --SO.sub.2heteroaryl, --NR.sub.aR.sub.b,
--NR.sub.aC(O)R.sub.b, --C(O)NR.sub.cR.sub.d,
--SO.sub.2NIZ.sub.cR.sub.d, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl;
[0124] each Z.sup.4 is independently selected from halogen,
--(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)carbocycle,
-halo(C.sub.1-C.sub.6)alkyl, --NO.sub.2, --CN, --OH, oxo,
.dbd.NOR.sub.a, thioxo, -aryl, -heterocycle, -heteroaryl,
--(C.sub.3-C.sub.7)halocarbocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.3-C.sub.7)carbocycle, --O(C.sub.3-C.sub.7)halocarbocycle,
--Oaryl, --Oheterocycle, --Oheteroaryl, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --S(C.sub.3-C.sub.7)halocarbocycle,
--Saryl, --Sheterocycle, --Sheteroaryl,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle, --S(O)aryl,
--S(O)heterocycle, --S(O)heteroaryl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, SO.sub.2aryl,
--SO.sub.2heterocycle, --SO.sub.2heteroaryl, --NR.sub.aR.sub.b,
--NR.sub.aC(O)R.sub.a, --C(O)NR.sub.cR.sub.d,
--SO.sub.2NIZ.sub.eR.sub.d, --NR.sub.aSO.sub.2NRA.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl;
[0125] each Z.sup.5 is independently selected from --NO.sub.2,
--CN, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --NR.sub.aSO.sub.2(C.sub.1-C.sub.6)alkyl,
--NR.sub.aSO.sub.2(C.sub.2-C.sub.6)alkenyl,
--NR.sub.aSO.sub.2(C.sub.2-C.sub.6)alkynyl,
--NR.sub.aSO.sub.2(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2aryl, --NR.sub.aSO.sub.2heteraryl,
--NR.sub.aSO.sub.2heteroaryl, --NR.sub.aSO.sub.2heterocycle,
--NR.sub.aC(O)alkyl, --NR.sub.aC(O)alkenyl, --NR.sub.aC(O)alkynyl,
--NR.sub.aC(O) (C.sub.3-C.sub.7)carbocycle,
--NR.sub.aC(O)(C.sub.3-C.sub.7)halocarbocycle, --NR.sub.aC(O)aryl,
--NR.sub.aC(O)heteroaryl, --NR.sub.aC(O)heterocycle,
NR.sub.aC(O)NIZ.sub.eR.sub.d and NR.sub.aC(O)OR.sub.b;
[0126] each Z.sup.6 is independently selected from --NO.sub.2,
--CN, --NR.sub.aR.sub.a, NR.sub.aC(O)R.sub.b, --C(O)NIU.sub.d,
--(C.sub.3-C.sub.7)halocarbocycle, -aryl, -heteroaryl,
-heterocycle, --Oaryl, -Oheteroaryl, --Oheterocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl,
--O(C.sub.3-C.sub.7)carbocycle, --Ohalo(C.sub.1-C.sub.6)alkyl,
--Saryl, --Sheteroaryl, --Sheterocycle,
--S(C.sub.3-C.sub.7)halocarbocycle, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --S(C.sub.1-C.sub.6)haloalkyl,
--S(O)aryl, --S(O)heteroaryl, --S(O)heterocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)halo(C.sub.1-C.sub.6)alkyl, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2halo(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--SO.sub.2NR.sub.eR.sub.d,
NR.sub.aSO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2aryl, --NR.sub.aSO.sub.2heteroaryl,
--NR.sub.aSO.sub.2heteroaryl, --NR.sub.aSO.sub.2NIZ.sub.eR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl;
[0127] each Z.sup.7 is independently selected from --NO.sub.2,
.dbd.NOR.sub.a, --CN, --(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.2-C.sub.6)alkenyl-Z.sup.12, --(C.sub.2-C.sub.6)alkenylOH,
--(C.sub.2-C.sub.6)alkyrryl-Z.sup.12,
--(C.sub.2-C.sub.6)alkynyl-OH,
--(C.sub.1-C.sub.6)haloalkyl-Z.sup.12,
--(C.sub.1-C.sub.6)haloalkylOH,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.12,
--(C.sub.3-C.sub.7)carbocycleOH, --(C.sub.3-C.sub.7)halocarbocycle,
--(C.sub.1-C.sub.6)alkylNRA.sub.t,
--(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, -aryl,
-heteroaryl, -heterocycle, --O(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--O(C.sub.2-C.sub.6)alkenyl, --O(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --Oaryl,
--O(C.sub.1-C.sub.6)allylNIZ.sub.eR.sub.d,
--O(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--O(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, --Oheteroaryl,
--Oheterocycle, --S(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--S(C.sub.2-C.sub.6)alkenyl, --S(C.sub.2-C.sub.6)alkynyl,
--S(C.sub.1-C.sub.6)haloalkyl, --S(C.sub.3-C.sub.7)carbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle,
--S(C.sub.1-C.sub.6)alkylNit.sub.cR.sub.a,
--S(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--S(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, --Saryl,
--Sheteroaryl, --Sheterocycle, --S(O)(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.2-C.sub.6)alkenyl, --S(O)(C.sub.2-C.sub.6)alkynyl,
--S(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.1-C.sub.6)alkylNRA.sub.J,
--S(O)(C.sub.1-C.sub.6)allylNR.sub.aC(O)R.sub.a,
--S(O)(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, --S(O)aryl,
--S(O)heteroaryl, --S(O)heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.2-C.sub.6)alkenyl,
--SO.sub.2(C.sub.2-C.sub.6)alkynyl,
--SO.sub.2(C.sub.1-C.sub.6)haloalkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkylNR.sub.eR.sub.a,
--SO.sub.2(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--SO.sub.2(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.aC(O)OR.sub.b,
--NR.sub.aC(O)NIZ.sub.eR.sub.d--NR.sub.aSO.sub.2R.sub.b,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --OS(O).sub.2R.sub.a,
--C(O)NR.sub.cR.sub.d, and --OC(O)NR.sub.cR.sub.d, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.3-C.sub.7)halocarbocycle, aryl,
heteroaryl and heterocycle of Z.sup.7, either alone or as part of a
group, is optionally substituted with one or more (e.g. 1, 2, 3, 4
or 5) halogen, --OH, --OR.sub.b, --CN, --NR.sub.aC(O).sub.2R.sub.b,
-heteroaryl, -heterocycle, --Oheteroaryl, -Oheterocycle,
--NHheteroaryl, --NHheterocycle, or
--S(O).sub.2NR.sub.cR.sub.d.
[0128] each Z.sup.8 is independently selected from --NO.sub.2 and
--CN;
[0129] each Z.sup.9 is independently selected from
--(C.sub.1-C.sub.6)alkyl and --O(C.sub.1-C.sub.6)alkyl;
[0130] each Z.sup.10 is independently selected from: [0131] i)
halo, oxo, thioxo, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.1-C.sub.6)alkyl-, --OH,
--O(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)haloalkyl, --SH,
--S(C.sub.1-C.sub.6)alkyl, --SO(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl, --NH.sub.2,
--NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)alk.sub.Y1).sub.2; [0132] ii)
(C.sub.1-C.sub.6)alkyl optionally substituted with --OH,
--O--(C.sub.1-C.sub.6)haloalkyl, or --O--(C.sub.1-C.sub.6)alkyl;
and [0133] iii) aryl, heterocycle and heteroaryl, which aryl,
heterocycle and heteroaryl is optionally substituted with halo,
(C.sub.1-C.sub.6)alkyl or COOH;
[0134] each Z.sup.11 is independently selected from Z.sup.10,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-C.sub.4)alkyl,
--C(.dbd.O)--N((C.sub.1-C.sub.4)alkyl).sub.2, --C(.dbd.O)-aryl,
--C(.dbd.O)-heterocycle and --C(.dbd.O)-heteroaryl;
[0135] each Z.sup.12 is independently selected from --NO.sub.2,
.dbd.NOR.sub.a, thioxo, -aryl, -heterocycle, -heteroaryl,
--(C.sub.3-C.sub.7)halocarbocycle, --(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)carbocycle, --Ohalo(C.sub.3-C.sub.7)carbocycle,
--Oaryl, --Oheterocycle, --Oheteroaryl, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --Shalo(C.sub.3-C.sub.7)carbocycle,
--Saryl, --Sheterocycle, --Sheteroaryl,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)halo(C.sub.3-C.sub.7)carbocycle, --S(O)aryl,
--S(O)heterocycle, --S(O)heteroaryl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, SO.sub.2aryl,
--SO.sub.2heterocycle, --SO.sub.2heteroaryl, --NR.sub.aR.sub.a,
--NR.sub.aC(O)R.sub.b, --C(O)NR.sub.cR.sub.d,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.aSO.sub.2NR-A.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl;
[0136] each Z.sup.13 is independently selected from --NO.sub.2,
--OH, .dbd.NOR.sub.a, --SH, --CN,
--(C.sub.3-C.sub.7)halocarbocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.2-C.sub.6)alkenyl, --O(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --Oaryl, --Oheteroaryl,
-Oheterocycle, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.2-C.sub.6)alkenyl, --S(C.sub.2-C.sub.6)alkynyl,
--S(C.sub.1-C.sub.6)haloalkyl, --S(C.sub.3-C.sub.7)carbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle, --Saryl, --Sheteroaryl,
--Sheterocycle, --S(O)(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.2-C.sub.6)alkenyl, --S(O)(C.sub.2-C.sub.6)alkynyl,
--S(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle, --S(O)aryl,
--S(O)heteroaryl, --S(O)heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.2-C.sub.6)alkenyl,
--SO.sub.2(C.sub.2-C.sub.6)alkynyl,
--SO.sub.2(C.sub.1-C.sub.6)haloalkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.cR.sub.d,
--NR.sub.aC(O)R.sub.a, --NR.sub.aC(O)OR.sub.b,
--NR.sub.aC(O)NR.sub.cR.sub.d--NR.sub.aSO.sub.2R.sub.b,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --OS(O).sub.2R.sub.a, --C(O)R.sub.a,
--C(O)OR.sub.b, --C(O)NR.sub.cR.sub.d, and --OC(O)NR.sub.cR.sub.d,
wherein any (C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
--(C.sub.3-C.sub.7)halocarbocycle, (C.sub.3-C.sub.7)carbocycle,
(C.sub.3-C.sub.7)halocarbocycle, aryl, heteroaryl and heterocycle
of Z.sup.13, either alone or as part of a group, is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, --OH,
--OR.sub.b, --CN, --NR.sub.aC(O).sub.2R.sub.b, heteroaryl,
heterocycle, --Oheteroaryl, --Oheterocycle, --NHheteroaryl,
--NHheterocycle, or --S(O).sub.2NR.sub.cR.sub.d;
[0137] each Z.sup.14 is independently selected from --NO.sub.2,
.dbd.NOR.sub.a, --CN, --(C.sub.3-C.sub.7)halocarbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2Oaryl and --OS(O).sub.2R.sub.a, wherein any
--(C.sub.3-C.sub.7)halocarbocycle of Z.sup.14, either alone or as
part of a group, is optionally substituted with one or more (e.g.
1, 2, 3, 4 or 5) halogen, --OH, --OR.sub.b, --CN,
--NR.sub.aC(O).sub.2R.sub.b, heteroaryl, heterocycle, -Oheteroaryl,
--Oheterocycle, --NHheteroaryl, --NHheterocycle, or
--S(O).sub.2NR.sub.cR.sub.d;
[0138] each R.sub.a is independently H, (C.sub.1-C.sub.6)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)carbocycle, heterocycle, aryl,
aryl(C.sub.1-C.sub.6)alkyl-, heteroaryl or
heteroaryl(C.sub.1-C.sub.6)alkyl-, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle, heterocycle,
aryl or heteroaryl of R.sub.a, either alone or as part of a group,
is optionally substituted by one or more (e.g. 1, 2, 3, 4 or 5)
halogen, OH and cyano;
[0139] each R.sub.b is independently --(C.sub.1-C.sub.6)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)carbocycle, heterocycle, aryl,
aryl(C.sub.1-C.sub.6)alkyl-, heteroaryl or
heteroaryl(C.sub.1-C.sub.6)alkyl-, wherein any
(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle,
heterocycle, aryl or heteroaryl of R.sub.b, either alone or as part
of a group, is optionally substituted by one or more (e.g. 1, 2, 3,
4 or 5) halogen, OH and cyano;
[0140] R.sub.c and R.sub.d are each independently selected from H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle, aryl,
aryl(C.sub.1-C.sub.6)alkyl-, heterocycle, heteroaryl and
heteroaryl(C.sub.1-C.sub.6)alkyl-, wherein any
(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle,
heterocycle, aryl and heteroaryl of R.sub.e or R.sub.d, either
alone or as part of a group, is optionally substituted by one or
more (e.g. 1, 2, 3, 4 or 5) halogen, OH and cyano; or 4 and R.sub.d
together with the nitrogen to which they are attached form a
heterocycle, wherein any heterocycle of R.sub.c and R.sub.d
together with the nitrogen to which they are attached is optionally
substituted by one or more (e.g. 1, 2, 3, 4 or 5) halogen, OH or
cyano;
[0141] each R.sub.e is independently selected from --OR.sub.a,
(C.sub.1-C.sub.6)alkyl and (C.sub.3-C.sub.7)carbocycle, wherein
(C.sub.1-C.sub.6)alkyl and (C.sub.3-C.sub.7)carbocycle is
substituted by one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.6 and
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1, --(C.sub.2-C.sub.6)haloalkyl, --(C.sub.2-C.sub.6)alkenyl
and --(C.sub.2-C.sub.6)alkynyl, wherein any
--(C.sub.2-C.sub.6)haloalkyl, --(C.sub.2-C.sub.6)alkenyl and
--(C.sub.2-C.sub.6)alkynyl is optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z', and aryl, heterocycle and
heteroaryl wherein aryl, heterocycle and heteroaryl is substituted
by one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.5;
[0142] each R.sub.f is independently selected from --R.sub.g,
--OR.sub.a, --(C.sub.1-C.sub.6)alkyl-Z.sup.6, --SO.sub.2R.sub.g,
--C(O)R.sub.g, C(O)OR.sub.g and --C(O)NR.sub.eR.sub.g; and
[0143] each R.sub.g is independently selected from H, --OR.sub.a,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle and heteroaryl, wherein
any (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle and heteroaryl of
R.sub.g is optionally substituted with one or more (e.g. 1, 2, 3, 4
or 5) Z.sup.1 groups;
[0144] or a salt thereof.
[0145] The invention also provides a pharmaceutical composition
comprising a compound of formula I or a pharmaceutically acceptable
salt thereof, in combination with a pharmaceutically acceptable
carrier.
[0146] The invention also provides method for treating (e.g.
preventing, mediating or inhibiting) the proliferation of the HIV
virus, treating AIDS or delaying the onset of AIDS or ARC symptoms
in a mammal (e.g. a human), comprising administering a compound of
formula I, or a pharmaceutically acceptable salt thereof, to the
mammal.
[0147] The invention also provides a compound of formula I, or a
pharmaceutically acceptable salt thereof for use in medical therapy
(e.g. for use in treating (e.g. preventing, mediating or
inhibiting) the proliferation of the HIV virus or AIDS or delaying
the onset of AIDS or ARC symptoms in a mammal (e.g. a human)).
[0148] The invention also provides a compound of formula I, or a
pharmaceutically acceptable salt thereof for use in the manufacture
of a medicament for treating (e.g. preventing, mediating or
inhibiting) the proliferation of the HIV virus or AIDS or delaying
the onset of AIDS or ARC symptoms in a mammal (e.g. a human).
[0149] The invention also provides a compound of formula I, or a
pharmaceutically acceptable salt thereof, for use in the
prophylactic or therapeutic treatment (e.g. prevention, mediation
or inhibiting) of the proliferation of the HIV virus or AIDS or for
use in the therapeutic treatment of delaying the onset of AIDS or
ARC symptoms.
[0150] The invention also provides processes and intermediates
disclosed herein that are useful for preparing compounds of formula
I or salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0151] Unless stated otherwise, the following terms and phrases as
used herein are intended to have the following meanings:
[0152] When trade names are used herein, applicants intend to
independently include the tradename product and the active
pharmaceutical ingredient(s) of the tradename product.
[0153] "Alkyl" is hydrocarbon containing normal, secondary or
tertiary atoms. For example, an alkyl group can have 1 to 20 carbon
atoms (i.e, (C.sub.1-C.sub.20)alkyl), 1 to 10 carbon atoms (i.e.,
(C.sub.1-C.sub.10)alkyl), 1 to 8 carbon atoms (i.e.,
(C.sub.1-C.sub.8)alkyl)or 1 to 6 carbon atoms (i.e.,
(C.sub.1-C.sub.6 alkyl). Examples of suitable alkyl groups include,
but are not limited to, methyl (Me, --CH.sub.3), ethyl (Et,
--CH.sub.2CH.sub.3), 1-propyl (n-Pr, n-propyl,
--CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3, and octyl
(--(CH.sub.2).sub.7CH.sub.3). "Alkyl" also refers to a saturated,
branched or straight chain hydrocarbon radical having two
monovalent radical centers derived by the removal of two hydrogen
atoms from the same or two different carbon atoms of a parent
alkane. For example, an alkyl group can have 1 to 10 carbon atoms
(i.e., (C.sub.1-C.sub.10)alkyl), or 1 to 6 carbon atoms (i.e.,
(C.sub.1-C.sub.6)alkyl) or 1-3 carbon atoms (i.e.,
(C.sub.1-C.sub.3)alkyl). Typical alkyl radicals include, but are
not limited to, methylene (--CH.sub.2--), 1,1-ethyl
(--CH(CH.sub.3)--), 1,2-ethyl (--CH.sub.2CH.sub.2--), 1,1-propyl
(--CH(CH.sub.2CH.sub.3)--), 1,2-propyl (--CH.sub.2CH(CH.sub.3)--),
1,3-propyl (--CH.sub.2CH.sub.2CH.sub.2--), 1,4-butyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and the like.
[0154] "Alkenyl" is a straight or branched hydrocarbon containing
normal, secondary or tertiary carbon atoms with at least one site
of unsaturation, i.e. a carbon-carbon, sp.sup.2 double bond. For
example, an alkenyl group can have 2 to 20 carbon atoms (i.e.,
C.sub.2-C.sub.20 alkenyl), 2 to 8 carbon atoms C.sub.2-C.sub.8
alkenyl), or 2 to 6 carbon atoms (i.e., C.sub.2-C.sub.6 alkenyl).
Examples of suitable alkenyl groups include, but are not limited
to, ethylene or vinyl (--CH.dbd.CH.sub.2), allyl
(--CH.sub.2CH.dbd.CH.sub.2), cyclopentenyl (--C.sub.5H.sub.7), and
5-hexenyl (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH.sub.2).
[0155] "Alkynyl" is a straight or branched hydrocarbon containing
normal, secondary or tertiary carbon atoms with at least one site
of unsaturation, i.e. a carbon-carbon, sp triple bond. For example,
an alkynyl group can have 2 to 20 carbon atoms (i.e.,
C.sub.2-C.sub.20 alkynyl), 2 to 8 carbon atoms (i.e.,
C.sub.2-C.sub.8 alkyne), or 2 to 6 carbon atoms (i.e.,
C.sub.2-C.sub.6 alkynyl). Examples of suitable alkynyl groups
include, but are not limited to, acetylenic (--C.ident.CH),
propargyl (--CH.sub.2C-mCH), and the like.
[0156] The term "halo" or "halogen" as used herein refers to
fluoro, chloro, bromo and iodo.
[0157] The term "haloalkyl" as used herein refers to an alkyl as
defined herein, wherein one or more hydrogen atoms are each
replaced by a halo substituent. For example, a
(C.sub.1-C.sub.6)haloalkyl is a (C.sub.1-C.sub.6)allyl wherein one
or more of the hydrogen atoms have been replaced by a halo
substituent. Such a range includes one halo substituent on the
alkyl group up to complete halogenation of the alkyl group.
[0158] The term "aryl" as used herein refers to a single aromatic
ring or a bicyclic or multicyclic ring. For example, an aryl group
can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12
carbon atoms. Aryl includes a phenyl radical or an ortho-fused
bicyclic or multicyclic radical having about 9 to 14 atoms in which
at least one ring is aromatic (e.g. an aryl fused to one or more
aryl or carbocycle). Such bicyclic or multicyclic rings may be
optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups
on any carbocycle portion of the bicyclic or multicyclic ring. It
is to be understood that the point of attachment of a bicyclic or
multicyclic radical, as defined above, can be at any position of
the ring including an aryl or a carbocycle portion of the ring.
Typical aryl groups include, but are not limited to, phenyl,
indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and
the like.
[0159] "Arylalkyl" refers to an alkyl radical as defined herein in
which one of the hydrogen atoms bonded to a carbon atom is replaced
with an aryl radical as described herein (i.e., an
aryl-alkyl-moiety). The alkyl group of the "arylalkyl" is typically
1 to 6 carbon atoms (i.e. aryl(C.sub.1-C.sub.6)alkyl). Arylalkyl
groups include, but are not limited to, benzyl, 2-phenylethan-1-yl,
1-phenylpropan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl and the
like.
[0160] The term "heteroaryl" as used herein refers to a single
aromatic ring or a multiple condensed ring. The term includes
single aromatic rings of from about 1 to 6 carbon atoms and about
1-4 heteroatoms selected from the group consisting of oxygen,
nitrogen and sulfur in the rings. The sulfur and nitrogen atoms may
also be present in an oxidized form provided the ring is aromatic.
Such rings include but are not limited to pyridyl, pyrimidinyl,
oxazolyl or furyl. The term also includes multiple condensed ring
systems (e.g. ring systems comprising 2 or 3 rings) wherein a
heteroaryl group, as defined above, can be fused with one or more
heteroaryls (e.g. naphthyridinyl), carbocycles (e.g.
5,6,7,8-tetrahydroquinolyl) or aryls (e.g. indazolyl) to form a
multiple condensed ring. Such multiple condensed rings may be
optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups
on the carbocycle portions of the condensed ring. It is to be
understood that the point of attachment of a heteroaryl multiple
condensed ring, as defined above, can be at any position of the
ring including a heteroaryl, aryl or a carbocycle portion of the
ring. Exemplary heteroaryls include but are not limited to pyridyl,
pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl,
indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl,
thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl,
indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl
benzofuranyl, benzimidazolyl and thianaphthenyl.
[0161] The term "heterocyclyl" or "heterocycle" as used herein
refers to a single saturated or partially unsaturated ring or a
multiple condensed ring system. The term includes single saturated
or partially unsaturated ring (e.g. 3, 4, 5, 6 or 7-membered ring)
from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms
selected from the group consisting of oxygen, nitrogen and sulfur
in the ring. The ring may be substituted with one or more (e.g. 1,
2 or 3) oxo groups and the sulfur and nitrogen atoms may also be
present in their oxidized forms. Such rings include but are not
limited to azetidinyl, tetrahydrofuranyl or piperidinyl. The term
also includes multiple condensed ring systems (e.g. ring systems
comprising 2 or 3 rings) wherein a heterocycle group (as defined
above) can be connected to two adjacent atoms (fused heterocycle)
with one or more heterocycles (e.g. decahydronapthyridinyl),
heteroaryls (e.g. 1,2,3,4-tetrahydronaphthyridinyl), carbocycles
(e.g. decahydroquinolyl) or aryls. It is to be understood that the
point of attachment of a heterocycle multiple condensed ring, as
defined above, can be at any position of the ring including a
heterocycle, heteroaryl, aryl or a carbocycle portion of the ring.
Exemplary heterocycles include, but are not limited to aziridinyl,
azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl,
morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl,
dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl,
1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl,
chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl,
1,3-benzodioxolyl and 1,4-benzodioxanyl.
[0162] The term "bridged-heterocycle" as used herein refers to a 4,
5, 6, 7 or 8-membered heterocycle as defined herein connected at
two non-adjacent atoms of the 4, 5, 6, 7 or 8-membered heterocycle
with one or more (e.g. 1 or 2) 3, 4, 5 or 6-membered heterocycles
or a (C.sub.3-C.sub.7)carbocycles as defined herein. Such
bridged-heterocycles include bicyclic and tricyclic ring systems
(e.g. 2-azabicyclo[2.2.1]heptane and
4-azatricyclo[4.3.1.1.sup.3,8]undecane).
[0163] The term "spiro-heterocycle" as used herein refers to a 3,
4, 5, 6, 7 or 8-membered heterocycle as defined herein connected to
one or more (e.g. 1 or 2) single atoms of the 3, 4, 5, 6, 7 or
8-membered heterocycle with one or more (e.g. 1 or 2) 3, 4, 5,
6-membered heterocycles or a (C.sub.3-C.sub.7)carbocycles as
defined herein. Such spiro-heterocycles include bicyclic and
tricyclic ring systems (e.g. 1,4-dioxaspiro[4.5]dec-7-enyl).
[0164] The term "macroheterocycle" as used herein refers to a
saturated or partially unsaturated 8, 9, 10, 11 or 12-membered ring
comprising about 5 to 11 carbon atoms and about 1 to 3 heteroatoms
selected from the group consisting of oxygen, nitrogen and sulfur
in the ring which may be optionally fused at two adjacent atoms of
the macroheterocycle to one or more (e.g. 1, 2 or 3) aryls,
carbocycles, heteroaryls or heterocycles. The macroheterocycle may
be substituted with one or more (e.g. 1, 2 or 3) oxo groups and the
sulfur and nitrogen atoms may also be present in their oxidized
forms.
[0165] "Heteroarylalkyl" refers to an alkyl radical as defined
herein in which one of the hydrogen atoms bonded to a carbon atom
is replaced with a heteroaryl radical as described herein (i.e., a
heteroaryl-alkyl-moiety). The alkyl group of the "heteroarylalkyl"
is typically 1 to 6 carbon atoms (i.e.
heteroaryl(C.sub.1-C.sub.6)alkyl).
[0166] Heteroarylalkyl groups include, but are not limited to
heteroaryl-CH.sub.2--, heteroaryl-CH(CH.sub.3)--,
heteroaryl-CH.sub.2CH.sub.2--, 2-(heteroarypethan-1-yl, and the
like, wherein the "heteroaryl" portion includes any of the
heteroaryl groups described above. One skilled in the art will also
understand that the heteroaryl group can be attached to the alkyl
portion of the heteroarylalkyl by means of a carbon-carbon bond or
a carbon-heteroatom bond, with the proviso that the resulting group
is chemically stable. Examples of heteroarylalkyls include by way
of example and not limitation 5-membered sulfur, oxygen, and/or
nitrogen containing heteroaryls such as thiazolylmethyl,
2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl,
thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or
nitrogen containing heteroaryls such pyridinylmethyl,
pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.
[0167] "Heterocyclylalkyl" refers to an alkyl radical as defined
herein in which one of the hydrogen atoms bonded to a carbon atom
is replaced with a heterocyclyl radical as described herein (i.e.,
a heterocyclyl-alkyl-moiety). The alkyl group of the
"heterocyclylalkyl" is typically 1 to 6 carbon atoms (i.e.
heterocyclyl(C.sub.1-C.sub.6)alkyl). Typical heterocyclylalkyl
groups include, but are not limited to heterocyclyl-CH.sub.2--,
heterocyclyl-CH(CH.sub.3)--, heterocyclyl-CH.sub.2CH.sub.2--,
2-(heterocyclypethari-1-yl, and the like, wherein the
"heterocyclyl" portion includes any of the heterocyclyl groups
described above. One skilled in the art will also understand that
the heterocyclyl group can be attached to the alkyl portion of the
heterocyclyl alkyl by means of a carbon-carbon bond or a
carbon-heteroatom bond, with the proviso that the resulting group
is chemically stable. Examples of heterocyclylalkyls include by way
of example and not limitation 5-membered sulfur, oxygen, and/or
nitrogen containing heterocycles such tetrahydrofuranylmethyl and
pyrroldinylmethyl, etc., and 6-membered sulfur, oxygen, and/or
nitrogen containing heterocycles such as piperidinylmethyl,
piperazinylmethyl, morpholinylmethyl, etc.
[0168] The term "carbocycle" or "carbocyclyl" refers to a saturated
(i.e., cycloalkyl) or partially unsaturated (e.g. cycloalkenyl,
cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms as a
monocycle or a multicyclic ring system. In one embodiment the
carbocycle is a monocycle comprising 3-6 ring carbons (i.e.
(C.sub.1-C.sub.6)carbocycle). Carbocycle includes multicyclic
carbocycles have 7 to 12 carbon atoms as a bicycle, and up to about
20 carbon atoms as a polycycle provided that the largest single
ring of a multicyclic carbocycle is 7 carbon atoms. The term
"spiro-bicyclic carbocycle" refers to a carbocycle bicyclic ring
system wherein the rings of the bicyclic ring system are connected
to a single carbon atom (e.g. spiropentane, spiro[4,5]decane,
spiro[4.5]decane, etc). The term "fused-bicyclic carbocycle" refers
to a carbocycle bicyclic ring system wherein the rings of the
bicyclic ring system are connected to two adjacent carbon atoms
such as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, or 9 or 10
ring atoms arranged as a bicyclo[5,6] or [6,6] system (e.g.
decahydronaphthalene, norsabinane, norcarane). The term
"bridged-bicyclic carbocycle" refers to a carbocycle bicyclic ring
system wherein the rings of the bicyclic ring system are connected
to two non-adjacent carbon atoms (e.g. norbornane,
bicyclo[2.2.2]octane, etc). The "carbocycle" or "carbocyclyl" may
be optionally substituted with one or more (e.g. 1, 2 or 3) oxo
groups. Non-limiting examples of monocyclic carbocycles include
cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,
1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,
1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.
[0169] The term "halocarbocycle" as used herein refers to a
carbocycle as defined herein, wherein one or more hydrogen atoms
are each replaced by a halo substituent. For example,
(C.sub.3-C.sub.7)halocarbocycle is a (C.sub.3-C.sub.7)carbocycle
wherein one or more of the hydrogen atoms have been replaced by a
halo substituent. Such a range includes one halo substituent on the
carbocycle group to complete halogenation of the carbocycle
group.
[0170] The term "macrocarbocycle" as used herein refers to a
saturated or partially unsaturated 8, 9, 10, 11 or 12-membered ring
comprising 8 to 12 carbon atoms which may be optionally fused at
two adjacent atoms of the macrocarbocycle to one or more (e.g. 1, 2
or 3) aryls, carbocycles, heteroaryls or heterocycles. The
macrocarbocycle may be substituted with one or more (e.g. 1, 2 or
3) oxo groups.
[0171] "Carbocyclylalkyl" refers to an alkyl radical as defined
herein in which one of the hydrogen atoms bonded to a carbon atom
is replaced with a carbocyclyl radical as described herein (i.e., a
carbocyclyl-alkyl-moiety). The alkyl group of the
"carbocyclylalkyl" is typically 1 to 6 carbon atoms (i.e.
carbocyclyl(C.sub.1-C.sub.6)alkyl). Typical carbocyclyl alkyl
groups include, but are not limited to carbocyclyl-CH.sub.2--,
carbocyclyl-CH(CH.sub.3)--, carbocyclyl-CH.sub.2CH.sub.2--,
2-(carbocyclyl)ethan-1-yl, and the like, wherein the "carbocyclyl"
portion includes any of the carbocyclyl groups described above.
[0172] It is to be understood that when a variable is substituted,
for example, as described by the phrase "(C.sub.1-C.sub.6)alkyl,
either alone or as part of a group, is optionally substituted", the
phrase means that the variable (C.sub.1-C.sub.6)alkyl can be
substituted when it is alone and that it can also be substituted
when the variable "(C.sub.1-C.sub.6)alkyl" is part of a larger
group such as for example an aryl(C.sub.1-C.sub.6)alkyl or a
--(C.sub.1-C.sub.6)allyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.-
7)carbocycle group. Similarly, when stated, other variables (e.g.
(C.sub.1-C.sub.6)alkenyl, (C.sub.1-C.sub.6)alkynyl, aryl,
heteroaryl, heterocycle, etc. . . . ) can also be substituted
"either alone or as part of a group."
[0173] It is to be understood that certain variables of formula I
that connect two chemical groups may be oriented in either
direction. Thus, for the X group of formula I (e.g. O, --C(O)--,
--C(O)O--, --S--, --S(O)--, --SO.sub.2-,
--(C.sub.1-C.sub.6)alkylO--, --(C.sub.1-C.sub.6)alkylC(O)--,
--(C.sub.1-C.sub.6)alkylC(O)O--, --(C.sub.1-C.sub.6)alkylS--,
--(C.sub.1-C.sub.6)alkylS(O)-- and
--(C.sub.1-C.sub.6)alkylSO.sub.2--) certain values of X that are
not symmetric can be oriented in either direction. For example, the
--C(O)O--, can be oriented as either --C(O)O-- or --OC(O)--,
relative to the groups it connects.
[0174] It is to be understood that the nitrogen that is included in
the core of the compound of formula I can be present in an oxidized
form. For example, the quinoline nitrogen of either G.sup.1 or
G.sup.2 of formula I can be an N-oxide. Accordingly, the invention
includes a compound of formula I (as defined in the summary of the
invention) or a salt or N-oxide thereof.
[0175] One skilled in the art will recognize that substituents and
other moieties of the compounds of formula I should be selected in
order to provide a compound which is sufficiently stable to provide
a pharmaceutically useful compound which can be formulated into an
acceptably stable pharmaceutical composition. Compounds of formula
I which have such stability are contemplated as falling within the
scope of the present invention.
[0176] The modifier "about" used in connection with a quantity is
inclusive of the stated value and has the meaning dictated by the
context (e.g., includes the degree of error associated with
measurement of the particular quantity).
[0177] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner. The term
"stereoisomers" refers to compounds which have identical chemical
constitution, but differ with regard to the arrangement of the
atoms or groups in space.
[0178] "Diastereomer" refers to a stereoisomer with two or more
centers or axes of chirality and whose molecules are not mirror
images of one another. Diastereomers typically have different
physical properties, e.g., melting points, boiling points, spectral
properties, and reactivities. Mixtures of diastereomers may
separate under high resolution analytical procedures such as
electrophoresis and chromatography.
[0179] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0180] Certain compounds of the invention can exist as
atropisomers. For example, it has been discovered that atropisomers
exist for certain substituents at the R.sup.4 position of formula I
as marked by an asterisk in the formula below.
##STR00003##
[0181] The chirality that results from the atropisomers at the
asterisk position is a feature of certain compounds of the
invention. Accordingly, the invention includes all atropisomers of
compounds of the invention including mixtures of atropisomers and
well as mixtures that are enriched in an atropisomer as well as
single atropisomers, which mixtures or compounds possess the useful
properties described herein.
[0182] In one embodiment, the compounds of the invention of formula
I are at least 60% a single atropisomer for the R.sup.4 substituent
at the asterisk position. In another embodiment, the compounds of
the invention of formula I are at least 70% a single atropisomer
for the R.sup.4 substituent at the asterisk position. In another
embodiment, the compounds of the invention of formula I are at
least 80% a single atropisomer for the R.sup.4 substituent at the
asterisk position. In another embodiment, the compounds of the
invention of formula I are at least 90% a single atropisomer for
the R.sup.4 substituent at the asterisk position. In another
embodiment, the compounds of the invention of formula I are at
least 95% a single atropisomer for the R.sup.4 substituent at the
asterisk position. In one embodiment the stereochemistry for the
R.sup.4 substituent at the carbon marked with an asterisk as shown
above for Formula I is the (R) stereochemistry. In another
embodiment the stereochemistry for the R.sup.4 substituent at the
carbon marked with an asterisk as shown above for Formula I is the
(S) stereochemistry.
[0183] The term "treatment" or "treating," to the extent it relates
to a disease or condition includes preventing the disease or
condition from occurring, inhibiting the disease or condition,
eliminating the disease or condition, and/or relieving one or more
symptoms of the disease or condition.
[0184] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds
(1994) John Wiley & Sons, Inc., New York. Many organic
compounds exist in optically active forms, i.e., they have the
ability to rotate the plane of plane-polarized light. In describing
an optically active compound, the prefixes (D and L) or (R and S)
are used to denote the absolute configuration of the molecule about
its chiral center(s). The prefixes d and 1 or (+) and (-) are
employed to designate the sign of rotation of plane-polarized light
by the compound, with (-) or 1 meaning that the compound is
levorotatory. A compound prefixed with (+) or d is dextrorotatory.
For a given chemical structure, these stereoisomers are identical
except that they are mirror images of one another. A specific
stereoisomer may also be referred to as an enantiomer, and a
mixture of such isomers is often called an enantiomeric mixture. A
50:50 mixture of enantiomers is referred to as a racemic mixture or
a racemate, which may occur where there has been no stereoselection
or stereospecificity in a chemical reaction or process. The terms
"racemic mixture" and "racemate" refer to an equimolar mixture of
two enantiomeric species, devoid of optical activity.
Protecting Groups
[0185] In the context of the present invention, protecting groups
include prodrug moieties and chemical protecting groups.
[0186] "Protecting group" refers to a moiety of a compound that
masks or alters the properties of a functional group or the
properties of the compound as a whole. Chemical protecting groups
and strategies for protection/deprotection are well known in the
art. See e.g., Protective Groups in Organic Chemistry, Theodora W.
Greene, John Wiley & Sons, Inc., New York, 1991. Protecting
groups are often utilized to mask the reactivity of certain
functional groups, to assist in the efficiency of desired chemical
reactions, e.g., making and breaking chemical bonds in an ordered
and planned fashion. Protection of functional groups of a compound
alters other physical properties besides the reactivity of the
protected functional group, such as the polarity, lipophilicity
(hydrophobicity), and other properties which can be measured by
common analytical tools. Chemically protected intermediates may
themselves be biologically active or inactive.
[0187] Protected compounds may also exhibit altered, and in some
cases, optimized properties in vitro and in vivo, such as passage
through cellular membranes and resistance to enzymatic degradation
or sequestration. In this role, protected compounds with intended
therapeutic effects may be referred to as prodrugs. Another
function of a protecting group is to convert the parental drug into
a prodrug, whereby the parental drug is released upon conversion of
the prodrug in vivo. Because active prodrugs may be absorbed more
effectively than the parental drug, prodrugs may possess greater
potency in vivo than the parental drug. Protecting groups are
removed either in vitro, in the instance of chemical intermediates,
or in vivo, in the case of prodrugs. With chemical intermediates,
it is not particularly important that the resulting products after
deprotection, e.g., alcohols, be physiologically acceptable,
although in general it is more desirable if the products are
pharmacologically innocuous.
[0188] Protecting groups are available, commonly known and used,
and are optionally used to prevent side reactions with the
protected group during synthetic procedures, i.e. routes or methods
to prepare the compounds of the invention. For the most part the
decision as to which groups to protect, when to do so, and the
nature of the chemical protecting group "PG" will be dependent upon
the chemistry of the reaction to be protected against (e.g.,
acidic, basic, oxidative, reductive or other conditions) and the
intended direction of the synthesis. PGs do not need to be, and
generally are not, the same if the compound is substituted with
multiple PG. In general, PG will be used to protect functional
groups such as carboxyl, hydroxyl, thio, or amino groups and to
thus prevent side reactions or to otherwise facilitate the
synthetic efficiency. The order of deprotection to yield free
deprotected groups is dependent upon the intended direction of the
synthesis and the reaction conditions to be encountered, and may
occur in any order as determined by the artisan.
[0189] Various functional groups of the compounds of the invention
may be protected. For example, protecting groups for OH groups
(whether hydroxyl, carboxylic acid, phosphonic acid, or other
functions) include "ether- or ester-forming groups". Ether- or
ester-forming groups are capable of functioning as chemical
protecting groups in the synthetic schemes set forth herein.
However, some hydroxyl and thio protecting groups are neither
ether-nor ester-forming groups, as will be understood by those
skilled in the art, and are included with amides, discussed
below.
[0190] A very large number of hydroxylprotecting groups and
amide-forming groups and corresponding chemical cleavage reactions
are described in Protective Groups in Organic Synthesis, Theodora
W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN
0-471-62301-6) ("Greene"). See also Kocienski, Philip J.;
Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994),
which is incorporated by reference in its entirety herein. In
particular Chapter 1, Protecting Groups: An Overview, pages 1-20,
Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol
Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting
Groups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages
155-184. For protecting groups for carboxylic acid, phosphonic
acid, phosphonate, sulfonic acid and other protecting groups for
acids see Greene as set forth below.
Stereoisomers
[0191] The compounds of the invention may have chiral centers,
e.g., chiral carbon or phosphorus atoms. The compounds of the
invention thus include racemic mixtures of all stereoisomers,
including enantiomers, diastereomers, and atropisomers. In
addition, the compounds of the invention include enriched or
resolved optical isomers at any or all asymmetric, chiral atoms. In
other words, the chiral centers apparent from the depictions are
provided as the chiral isomers or racemic mixtures. Both racemic
and diastereomeric mixtures, as well as the individual optical
isomers isolated or synthesized, substantially free of their
enantiomeric or diastereomeric partners, are all within the scope
of the invention. The racemic mixtures can be separated into their
individual, substantially optically pure isomers through well-known
techniques such as, for example, the separation of diastereomeric
salts formed with optically active adjuncts, e.g., acids or bases
followed by conversion back to the optically active substances. In
most instances, the desired optical isomer is synthesized by means
of stereospecific reactions, beginning with the appropriate
stereoisomer of the desired starting material.
[0192] The compounds of the invention can also exist as tautomeric
isomers in certain cases. Although only one delocalized resonance
structure may be depicted, all such forms are contemplated within
the scope of the invention. For example, ene-amine tautomers can
exist for purine, pyrimidine, imidazole, guanidine, amidine, and
tetrazole systems and all their possible tautomeric forms are
within the scope of the invention.
Salts and Hydrates
[0193] Examples of pharmaceutically acceptable salts of the
compounds of the invention include salts derived from an
appropriate base, such as an alkali metal (for example, sodium), an
alkaline earth metal (for example, magnesium), ammonium and
NX.sub.4.sup.+ (wherein X is C.sub.1-C.sub.4 alkyl).
Pharmaceutically acceptable salts of a hydrogen atom or an amino
group include for example salts of organic carboxylic acids such as
acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic,
isethionic, lactobionic and succinic acids; organic sulfonic acids,
such as methanesulfonic, ethanesulfonic, benzenesulfonic and
p-toluenesulfonic acids; and inorganic acids, such as hydrochloric,
hydrobromic, sulfuric, phosphoric and sulfamic acids.
Pharmaceutically acceptable salts of a compound of a hydroxy group
include the anion of said compound in combination with a suitable
cation such as Na.sup.+ and NX.sub.4.sup.+ (wherein X is
independently selected from H or a C.sub.1-C.sub.4 alkyl
group).
[0194] For therapeutic use, salts of active ingredients of the
compounds of the invention will typically be pharmaceutically
acceptable, i.e. they will be salts derived from a physiologically
acceptable acid or base. However, salts of acids or bases which are
not pharmaceutically acceptable may also find use, for example, in
the preparation or purification of a compound of formula I or
another compound of the invention. All salts, whether or not
derived from a physiologically acceptable acid or base, are within
the scope of the present invention.
[0195] Metal salts typically are prepared by reacting the metal
hydroxide with a compound of this invention. Examples of metal
salts which are prepared in this way are salts containing Li.sup.+,
Na.sup.+ and K.sup.+. A less soluble metal salt can be precipitated
from the solution of a more soluble salt by addition of the
suitable metal compound.
[0196] In addition, salts may be formed from acid addition of
certain organic and inorganic acids, e.g., HCl, HBr,
H.sub.2SO.sub.4, H3PO.sub.4 or organic sulfonic acids, to basic
centers, typically amines, or to acidic groups. Finally, it is to
be understood that the compositions herein comprise compounds of
the invention in their un-ionized, as well as zwitterionic form,
and combinations with stoichiometric amounts of water as in
hydrates.
[0197] Also included within the scope of this invention are the
salts of the parental compounds with one or more amino acids. Any
of the natural or unnatural amino acids are suitable, especially
the naturally-occurring amino acids found as protein components,
although the amino acid typically is one bearing a side chain with
a basic or acidic group, e.g., lysine, arginine or glutamic acid,
or a neutral group such as glycine, serine, threonine, alanine,
isoleucine, or leucine.
[0198] Specific values listed below for radicals, substituents, and
ranges in the embodiments of the invention are for illustration
only; they do not exclude other defined values or other values
within defined ranges for the radicals and substituents.
Isotopes
[0199] It is understood by one skilled in the art that this
invention also includes any compound claimed that may be enriched
at any or all atoms above naturally occurring isotopic ratios with
one or more isotopes such as, but not limited to, deuterium
(.sup.2H or D). As a non-limiting example, a --CH.sub.3 group may
be substituted with --CD.sub.3.
Compounds of formula I.
[0200] A specific group of compounds of formula I are compounds of
formula Ia.
##STR00004##
[0201] Another specific group of compounds of formula I are
compounds of formula Ib.
##STR00005##
[0202] Another specific group of compounds of formula I are
compounds of formula Ic.
##STR00006##
[0203] Another specific group of compounds of formula I are
compounds of formula Id.
##STR00007##
[0204] Another specific group of compounds of formula I are
compounds of formula Ie.
##STR00008##
[0205] Another specific group of compounds of formula I are
compounds of formula If.
##STR00009##
[0206] Another specific group of compounds of formula I are
compounds of formula Ig.
##STR00010##
[0207] Another specific group of compounds of formula I are
compounds of formula Ih.
##STR00011##
[0208] Another specific group of compounds of formula I are
compounds of formula Ii.
##STR00012##
[0209] Another specific group of compounds of formula I are
compounds of formula Ij.
##STR00013##
[0210] Another specific group of compounds of formula I are
compounds of formula Ik.
##STR00014##
[0211] Another specific group of compounds of formula I are
compounds of formula Im.
##STR00015##
[0212] Another specific group of compounds of formula I are
compounds of formula In.
##STR00016##
[0213] wherein the ring W is heteroaryl optionally substituted with
one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups.
[0214] Another specific group of compounds of formula I are
compounds of formula In.
##STR00017##
[0215] wherein the ring W is heteroaryl optionally substituted with
one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups.
[0216] Another specific group of compounds of formula I are
compounds of formula Ip.
##STR00018##
[0217] wherein the ring W is heteroaryl optionally substituted with
one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups.
[0218] Another specific group of compounds of formula I are
compounds of formula Iq.
##STR00019##
[0219] wherein the ring W is heteroaryl optionally substituted with
one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups.
[0220] Another specific group of compounds of formula I are
compounds of formula Ir.
##STR00020##
[0221] Another specific group of compounds of formula I are
compounds of formula Is.
##STR00021##
[0222] Another specific group of compounds of formula I are
compounds of formula It.
##STR00022##
[0223] Another specific group of compounds of formula I are
compounds of formula Iu.
##STR00023##
[0224] wherein the ring W is heteroaryl optionally substituted with
one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups.
[0225] Specific values listed below are values for compounds of
formula I as well as the compounds of formula Ia, Ib, Ic, Id, Ie,
If, Ig, Ih, Ii, Ij, Ik, Im, In, Io, Ip, Iq, Ir, Is, It and Iu.
[0226] A specific group of compounds of formula I are compounds
wherein at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.3',
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 or R.sup.13 is selected
from R.sup.1b, R.sup.2b, R.sup.3b, R.sup.3b', R.sup.4b, R.sup.5b,
R.sup.6b, R.sup.7b, R.sup.8b and R.sup.13b.
[0227] Another specific group of compounds of formula I are
compounds wherein at least two of R.sup.1, R.sup.2, R.sup.3,
R.sup.3', R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 or R.sup.13
is selected from R.sup.1b, R.sup.2b, R.sup.3b, R.sup.3b', R.sup.4b,
R.sup.5b, R.sup.6b, R.sup.7b, R.sup.8b or R.sup.13b.
[0228] Another specific group of compounds of formula I are
compounds wherein at least three of R.sup.1, R.sup.2, R.sup.3,
R.sup.3', R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 or R.sup.13
is selected from R.sup.1b, R.sup.2b, R.sup.3b, R.sup.3b', R.sup.4b,
R.sup.5b, R.sup.6b, R.sup.7b, R.sup.8b or R.sup.13b.
[0229] Another specific group of compounds of formula I are
compounds wherein at least four of R.sup.1, R.sup.2, R.sup.3,
R.sup.3', R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 or R.sup.13
is selected from R.sup.1b, R.sup.2b, R.sup.3b, R.sup.3b', R.sup.4b,
R.sup.5b, R.sup.6b, R.sup.7b, R.sup.8b or R.sup.13b.
[0230] Another specific group of compounds of formula I are
compounds wherein at least five of R.sup.1, R.sup.2, R.sup.3,
R.sup.3', R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 or R.sup.13
is selected from R.sup.1b, R.sup.2b, R.sup.3b, R.sup.3b', R.sup.4b,
R.sup.5b, R.sup.6b, R.sup.7b, R.sup.8b or R.sup.13b.
[0231] Another specific group of compounds of formula I are
compounds wherein at least six of R.sup.1, R.sup.2, R.sup.3,
R.sup.3', R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 or R.sup.13
is selected from R.sup.1b, R.sup.2b, R.sup.3b, R.sup.3b', R.sup.4b,
R.sup.5b, R.sup.6b, R.sup.7b, R.sup.8b or R.sup.13b.
[0232] Another specific group of compounds of formula I are
compounds wherein at least seven of R.sup.1, R.sup.2, R.sup.3,
R.sup.3', R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 or R.sup.13
is selected from R.sup.1b, R.sup.2b, R.sup.3b, R.sup.3b', R.sup.4b,
R.sup.5b, R.sup.6b, R.sup.7b, R.sup.8b or R.sup.13b.
[0233] Another specific group of compounds of formula I are
compounds wherein at least eight of R.sup.1, R.sup.2, R.sup.3,
R.sup.3', R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 or R.sup.13
is selected from R.sup.1b, R.sup.2b, R.sup.3b, R.sup.3b', R.sup.4b,
R.sup.5b, R.sup.6b, R.sup.7b, R.sup.8b or R.sup.13b.
[0234] Another specific group of compounds of formula I are
compounds wherein at least nine of R.sup.1, R.sup.2, R.sup.3,
R.sup.3', R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 or R.sup.13
is selected from R.sup.1b, R.sup.2b, R.sup.3b, R.sup.3b', R.sup.4b,
R.sup.5b, R.sup.6b, R.sup.7b, R.sup.8b or R.sup.13b.
[0235] Another specific group of compounds of formula I are
compounds wherein R.sup.1, R.sup.2, R.sup.3, R.sup.3', R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.13 is selected from
R.sup.1b, R.sup.2b, R.sup.3b, R.sup.3b', R.sup.4b, R.sup.5b,
R.sup.6b, R.sup.7, R.sup.8b and R.sup.13b.
[0236] A specific value for R.sup.3 is R.sup.3b.
[0237] A specific value for R.sup.3b is
--OC(CH.sub.3).sub.2CH.sub.2OH, --OC(CH.sub.3).sub.2CH.sub.2OH,
--O(C.sub.1-C.sub.6)alkyl-O--C(O)--NH.sub.2,
--O(C.sub.1-C.sub.6)alkyl-O--C(O)--N(CH.sub.3).sub.2 or
--O(C.sub.1-C.sub.6)alkyl-O--C(O)--NH(phenyl).
[0238] Another specific value for R.sup.3b is
--(C.sub.1-C.sub.6)alkylOH or
--O(C.sub.1-C.sub.6)allyl-O--C(O)--NR.sub.clt.sub.d.
[0239] Another specific value for R.sup.3 is R.sup.3a.
[0240] A specific value for R.sup.3a is (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl or --O(C.sub.1-C.sub.6)alkyl, wherein any
(C.sub.1-C.sub.6)alkyl or (C.sub.2-C.sub.6)alkenyl of R.sup.3a is
optionally substituted with one or more groups selected from
--O(C.sub.1-C.sub.6)alkyl, halo, oxo and --CN.
[0241] Another specific value for R.sup.3a is --OC(CH.sub.3).
[0242] A specific value for R.sup.3' is R.sup.3b'.
[0243] A specific value for R.sup.3b' is (C.sub.1-C.sub.6)alkyl or
--O(C.sub.1-C.sub.6)alkyl.
[0244] A specific value for R.sup.3' is R.sup.3a'.
[0245] A specific value for R.sup.3a' is H.
[0246] A specific group of compounds of formula I are compounds
wherein R.sup.3b and R.sup.3b' together with the carbon to which
they are attached form a (C.sub.3-C.sub.7)carbocycle or
heterocycle, wherein the (C.sub.3-C.sub.7)carbocycle or heterocycle
is optionally substituted with one or more Z.sup.1 groups.
[0247] Another specific group of compounds of formula I are
compounds wherein R.sup.3b and R.sup.3b' together with the carbon
to which they are attached form a (C.sub.3-C.sub.7)carbocycle or a
4, 5 or 6-membered heterocycle, wherein the
(C.sub.3-C.sub.6)carbocycle or the 4, 5 or 6-membered heterocycle
is optionally substituted with one or more Z.sup.1 groups.
[0248] Another specific group of compounds of formula I are
compounds wherein Rab and R.sup.3b' together with the carbon to
which they are attached form a (C.sub.4-C.sub.6)carbocycle or a 5
or 6-membered heterocycle, wherein the (C.sub.4-C.sub.6)carbocycle
or the 5 or 6-membered heterocycle is optionally substituted with
one or more Z.sup.1 groups.
[0249] Another specific group of compounds of formula I are
compounds wherein Rab and R.sup.3b' together with the carbon to
which they are attached form a 5 or 6-membered heterocycle, wherein
the 5 or 6-membered heterocycle is optionally substituted with one
or more Z.sup.1 groups.
[0250] Another specific group of compounds of formula I are
compounds wherein Rab and R.sup.3b' together with the carbon to
which they are attached form a tetrahydropyran or tetrahydrofuran
optionally substituted with one or more Z.sup.1 groups.
[0251] Another specific group of compounds of formula I are
compounds wherein Rab and R.sup.3b' together with the carbon to
which they are attached form:
##STR00024##
[0252] each of which is optionally substituted with one or more
Z.sup.1 groups, and wherein "*" denotes the point of attachment to
the carbon of the compound of formula I.
[0253] A specific value for R.sup.4 is R.sup.4b.
[0254] A specific value for R.sup.4b is (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl or
(C.sub.2-C.sub.6)alkynyl are each optionally substituted with one
or more Z.sup.1 groups.
[0255] Another specific value for R.sup.4b is:
##STR00025##
[0256] optionally substituted with one or more Z.sup.1 groups.
[0257] Another specific value for R.sup.4b is
(C.sub.3-C.sub.7)carbocycle, wherein (C.sub.3-C.sub.7)carbocycle is
optionally substituted with one or more Z.sup.1 groups, or wherein
two Z.sup.1 groups together with the atom or atoms to which they
are attached optionally form a (C.sub.3-C.sub.6)carbocycle or
5-6-membered heterocycle.
[0258] Another specific value for R.sup.4b is:
##STR00026##
[0259] each of which is optionally substituted with one or more
Z.sup.1 groups.
[0260] Another specific value for R.sup.4b is aryl, heterocycle or
heteroaryl, wherein aryl, heterocycle or heteroaryl are each
independently substituted with one or more Z.sup.7 groups and
optionally substituted with one or more Z.sup.1 groups.
[0261] Another specific value for R.sup.4b is:
##STR00027## ##STR00028##
[0262] Another specific value for R.sup.4 is R.sup.4a.
[0263] A specific value for R.sup.4a is:
##STR00029## ##STR00030##
[0264] A specific group of compounds of formula I are compounds
wherein R.sup.4 and R.sup.3 together with the atoms to which they
are attached form a macroheterocycle or a macrocarbocycle, wherein
any macroheterocycle or macrocarbocycle of R.sup.4 and R.sup.3
together with the atoms to which they are attached may be
optionally substituted with one or more Z.sup.1 groups; and
R.sup.3' is H, (C.sub.1-C.sub.6)alkyl or
--O(C.sub.1-C.sub.6)alkyl.
[0265] Another specific group of compounds of formula I are
compounds wherein R.sup.4 and R.sup.3 together with the atoms to
which they are attached form a macroheterocycle or a
macrocarbocycle, wherein any macroheterocycle or macrocarbocycle of
R.sup.4 and R.sup.3 together with the atoms to which they are
attached may be optionally substituted with one or more Z.sup.1
groups; and R.sup.3' is H.
[0266] Another specific group of compounds of formula I are
compounds wherein R.sup.4 and R.sup.3 together with the atoms to
which they are attached form the macroheterocycle or a
macrocarbocycle which is further fused to a Z group;
##STR00031##
[0267] wherein:
[0268] Z is aryl, heteroaryl or (C.sub.3-C.sub.6)carbocycle;
[0269] n3 is 2, 3 or 4;
[0270] W.sup.1 and W.sup.2 are each independently O, NH or
CH.sub.2; and
[0271] wherein "*" denotes the R.sup.4 point of attachment of the
macroheterocycle or macrocarbocycle to the compound of formula I
and "**" denotes the R.sup.3 point of attachment of the
macroheterocycle or macrocarbocycle to the compound of formula I,
and wherein the macroheterocycle or a macrocarbocycle is optionally
substituted with one or more Z.sup.1 groups.
[0272] Another specific group of compounds of formula I are
compounds wherein, R.sup.4 and R.sup.3 together with the atoms to
which they are attached form the macroheterocycle:
##STR00032##
[0273] wherein:
[0274] n1 is 3 or 4; n2 is 2, 3 or 4; n3 is 2, 3 or 4; W is O, NH
or N(C.sub.1-C.sub.4)alkyl; and wherein "*" denotes the R.sup.4
point of attachment of the macroheterocycle to the compound of
formula I and "**" denotes the R.sup.3 point of attachment of the
macroheterocycle to the compound of formula I; and wherein the
macroheterocycle or a macrocarbocycle is optionally substituted
with one or more Z.sup.1 groups.
[0275] A specific value for R.sup.1 is R.sup.1b.
[0276] Another specific value R.sup.1 is R.sup.1a.
[0277] A specific value for R.sup.1a is H or halo.
[0278] A specific value for R.sup.2 is R.sup.2b.
[0279] Another specific value R.sup.2 is R.sup.2a.
[0280] A specific value for R.sup.2a is H, halo or --CH.sub.3.
[0281] Another specific value for R.sup.2a is --Cl.
[0282] A specific value for R.sup.5 is R.sup.5b.
[0283] Another specific value for R.sup.5 is R.sup.5a.
[0284] A specific value for R.sup.5a is H.
[0285] A specific value for R.sup.6 is R.sup.6b.
[0286] Another specific value for R.sup.6 is R.sup.6a.
[0287] A specific value for R.sup.6a is H.
[0288] A specific value for R.sup.7 is R.sup.6b.
[0289] Another specific value for R.sup.7 is le.sup.a.
[0290] A specific value for R.sup.7a is H, --CH.sub.3, CF.sub.3 or
halogen.
[0291] A specific value for R.sup.8 is R.sup.8b.
[0292] Another specific value for R.sup.8 is R.sup.8a.
[0293] Another specific value for R.sup.8a is H.
[0294] A specific group of compounds of formula I are compounds
wherein R.sup.ob is selected from:
[0295] a) (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl and
(C.sub.2-C.sub.6)alkynyl, wherein (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0296] b) (C.sub.3-C.sub.14)carbocycle, wherein
(C.sub.3-C.sub.14)carbocycle is optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0297] c) Spiro-heterocycle and bridged-heterocycle, wherein
spiro-heterocycle and bridged-heterocycle is optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups; and
[0298] d) aryl, heterocycle and heteroaryl, wherein aryl,
heterocycle and heteroaryl are each independently substituted with
one or more Z.sup.7 groups and optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups.
[0299] Another specific group of compounds of formula I are
compounds wherein Rob is selected from:
[0300] a) (C.sub.1-C.sub.6)allyl, (C.sub.2-C.sub.6)alkenyl and
(C.sub.2-C.sub.6)alkynyl, wherein (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0301] b) (C.sub.3-C.sub.14)carbocycle, wherein
(C.sub.3-C.sub.14)carbocycle is optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups, wherein two Z.sup.1
groups together with the atom or atoms to which they are attached
optionally form a (C.sub.3-C.sub.7)carbocycle or heterocycle;
and
[0302] c) aryl, heterocycle and heteroaryl, wherein aryl,
heterocycle and heteroaryl are each independently substituted with
one or more Z.sup.7 groups and optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups.
[0303] Another specific group of compounds of formula I are
compounds wherein Rob is selected from:
[0304] a) (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl and
(C.sub.2-C.sub.6)alkynyl, wherein (C.sub.1-C.sub.6)allyl,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0305] b) (C.sub.3-C.sub.14)carbocycle, wherein
(C.sub.3-C.sub.14)carbocycle is optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups; and
[0306] c) aryl, heterocycle and heteroaryl, wherein aryl,
heterocycle and heteroaryl are each independently substituted with
one or more Z.sup.7 groups and optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups.
[0307] Another specific group of compounds of formula I are
compounds wherein R.sup.3 is (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl or --O(C.sub.1-C.sub.6)alkyl, wherein any
(C.sub.1-C.sub.6)alkyl or (C.sub.2-C.sub.6)alkenyl of R.sup.3 is
optionally substituted with one or more groups selected from
--O(C.sub.1-C.sub.6)alkyl, halo, oxo and CN, and wherein R.sup.3'
is H.
[0308] Another specific value for R.sup.3 is
--O(C.sub.1-C.sub.6)alkyl.
[0309] Another specific value for R.sup.3 is --OtBu.
[0310] Another specific value for R.sup.3' is H.
[0311] Another specific value for R.sup.2 is halo, H or
--CH.sub.3.
[0312] Another specific value for R.sup.2 is chloro or
--CH.sub.3.
[0313] Another specific value for R.sup.2 is --CH.sub.3.
[0314] Another specific value for R.sup.1 is H.
[0315] Another specific value for R.sup.6 is H.
[0316] Another specific value for R.sup.5 is H or
(C.sub.1-C.sub.6)alkyl.
[0317] Another specific value for R.sup.5 is H or --CH.sub.3.
[0318] Another specific value for R.sup.5 is H.
[0319] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from:
[0320] a) aryl, heterocycle and heteroaryl, wherein aryl,
heterocycle and heteroaryl are each optionally substituted with one
or more groups each independently selected from halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, --OH,
--O(C.sub.1-C.sub.6)alkyl, --SH, --S(C.sub.1-C.sub.6)alkyl,
--NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)alk.sub.Y1).sub.2, wherein
(C.sub.1-C.sub.6)alkyl is optionally substituted with hydroxy,
--O(C.sub.1-C.sub.6)alkyl, cyano or oxo; and
[0321] b) (C.sub.3-C.sub.14)carbocycle, wherein
(C.sub.3-C.sub.14)carbocycle is optionally substituted with one or
more Z.sup.1 groups, wherein two Z.sup.1 groups together with the
atom or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle; and
[0322] c) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle
and bridged-heterocycle, wherein aryl, heteroaryl,
spiro-heterocycle, fused-heterocycle and bridged-heterocycle are
each independently substituted with one or more Z.sup.7 groups and
optionally substituted with one or more Z.sup.1 groups.
[0323] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from:
[0324] a) aryl, heterocycle and heteroaryl, wherein aryl,
heterocycle and heteroaryl are each optionally substituted with one
or more groups each independently selected from halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloallyl, --OH,
--O(C.sub.1-C.sub.6)alkyl, --SH, --S(C.sub.1-C.sub.6)alkyl,
--NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)alic.sub.Y1).sub.2, wherein
(C.sub.1-C.sub.6)alkyl is optionally substituted with hydroxy,
--O(C.sub.1-C.sub.6)alkyl, cyano or oxo;
[0325] b) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle
and bridged-heterocycle, wherein spiro-heterocycle,
fused-heterocycle and bridged-heterocycle are each independently
substituted with one or more Z.sup.7 groups and optionally
substituted with one or more Z.sup.1 groups.
[0326] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from:
[0327] a) aryl, heterocycle and heteroaryl, wherein aryl,
heterocycle and heteroaryl are each optionally substituted with one
or more groups each independently selected from halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, --OH,
--O(C.sub.1-C.sub.6)alkyl, --SH, --S(C.sub.1-C.sub.6)alkyl,
--NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)alkyl).sub.2, wherein (C.sub.1-C.sub.6)alkyl
is optionally substituted with hydroxy, --O(C.sub.1-C.sub.6)alkyl,
cyano or oxo; and
[0328] b) aryl, heteroaryl and fused-heterocycle, wherein aryl,
heteroaryl and fused-heterocycle are each independently substituted
with one or more Z.sup.7 groups and optionally substituted with one
or more Z.sup.1 groups.
[0329] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from:
[0330] a) heterocycle, wherein heterocycle is optionally
substituted with one or more groups each independently selected
from halo, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.r C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, --OH,
--O(C.sub.1-C.sub.6)alkyl, --SH, --S(C.sub.1-C.sub.6)alkyl,
--NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)alkyl).sub.2, wherein (C.sub.1-C.sub.6)alkyl
is optionally substituted with hydroxy, --O(C.sub.1-C.sub.6)alkyl,
cyano or oxo; and
[0331] b) fused-heterocycle, wherein fused-heterocycle is
substituted with one or more Z.sup.7 groups and optionally
substituted with one or more Z.sup.1 groups.
[0332] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from:
[0333] a) bicyclic aryl, tricyclic aryl, bicyclic heterocycle,
tricyclic heterocycle, bicyclic heteroaryl and tricyclic
heteroaryl, wherein bicyclic aryl, tricyclic aryl, bicyclic
heterocycle, tricyclic heterocycle, bicyclic heteroaryl and
tricyclic heteroaryl are each optionally substituted with one or
more groups each independently selected from halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, --OH,
--O(C.sub.1-C.sub.6)alkyl, --SH, --S(C.sub.1-C.sub.6)alkyl,
--NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)alkyl).sub.2, wherein (C.sub.1-C.sub.6)alkyl
is optionally substituted with hydroxy, cyano or oxo; and
[0334] b) bicyclic aryl, tricyclic aryl, bicyclic heteroaryl,
tricyclic heteroaryl bicyclic fused-heterocycle, and tricyclic
fused-heterocycle, wherein bicyclic aryl, tricyclic aryl, bicyclic
heteroaryl, tricyclic heteroaryl bicyclic fused-heterocycle and
tricyclic fused-heterocycle are each independently substituted with
one or more Z.sup.7 groups and optionally substituted with one or
more Z.sup.1 groups.
[0335] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from:
[0336] a) bicyclic heterocycle and tricyclic heterocycle, wherein
bicyclic heterocycle and tricyclic heterocycle are each optionally
substituted with one or more groups each independently selected
from halo, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
C.sub.6)haloallql, (C.sub.3-C.sub.7)cycloalkyl, --OH,
--O(C.sub.1-C.sub.6)alkyl, --SH, --S(C.sub.1-C.sub.6)alkyl,
--NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)alkyl).sub.2, wherein (C.sub.1-C.sub.6)alkyl
is optionally substituted with hydroxy, --O(C.sub.1-C.sub.6)alkyl,
cyano or oxo; and
[0337] b) bicyclic fused-heterocycle and tricyclic
fused-heterocycle, wherein bicyclic fused-heterocycle and tricyclic
fused-heterocycle fused-heterocycle are each substituted with one
or more Z.sup.7 groups and optionally substituted with one or more
Z.sup.1 groups.
[0338] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from:
[0339] a) bicyclic heterocycle, tricyclic heterocycle, bicyclic
heteroaryl and tricyclic heteroaryl wherein bicyclic heterocycle,
tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl
are each optionally substituted with one or more groups each
independently selected from halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)haloallyl,
(C.sub.3-C.sub.7)cycloalkyl, --OH, --O(C.sub.1-C.sub.6)alkyl, --SH,
--S(C.sub.1-C.sub.6)alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl
and --N((C.sub.1-C.sub.6)alkyl).sub.2, wherein
(C.sub.1-C.sub.6)alkyl is optionally substituted with hydroxy,
--O(C.sub.1-C.sub.6)alkyl, cyano or oxo; and
[0340] b) bicyclic fused-heterocycle and tricyclic
fused-heterocycle, wherein bicyclic fused-heterocycle and tricyclic
fused-heterocycle fused-heterocycle are each substituted with one
or more Z.sup.7 groups and optionally substituted with one or more
Z.sup.1 groups.
[0341] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from:
[0342] a) tricyclic heterocycle, wherein tricyclic heterocycle is
optionally substituted with one or more groups each independently
selected from halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)cycloalkyl, --OH, --O(C.sub.1-C.sub.6)alkyl, --SH,
--S(C.sub.1-C.sub.6)alkyl, --NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl
and --N((C.sub.1-C.sub.6)alkyl).sub.2, wherein
(C.sub.1-C.sub.6)alkyl is optionally substituted with hydroxy,
--O(C.sub.1-C.sub.6)alkyl, cyano or oxo; and
[0343] b) tricyclic fused-heterocycle wherein tricyclic
fused-heterocycle is substituted with one or more Z.sup.7 groups
and optionally substituted with one or more Z.sup.1 groups.
[0344] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from:
[0345] a) (C.sub.3-C.sub.14)carbocycle, wherein
(C.sub.3-C.sub.14)carbocycle is optionally substituted with one or
more Z.sup.1 groups, wherein two Z.sup.1 groups together with the
atom or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle; and
[0346] b) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle
and bridged-heterocycle, wherein aryl, heteroaryl or
spiro-heterocycle, fused-heterocycle and bridged-heterocycle are
each independently substituted with one or more Z.sup.7 groups and
optionally substituted with one or more Z.sup.1 groups.
[0347] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from aryl, heteroaryl,
spiro-heterocycle, fused-heterocycle and bridged-heterocycle,
wherein spiro-heterocycle, fused-heterocycle and
bridged-heterocycle are each independently substituted with one or
more Z.sup.7 groups and optionally substituted with one or more
Z.sup.1 groups.
[0348] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from aryl, heteroaryl and
fused-heterocycle, wherein aryl, heteroaryl and fused-heterocycle
are each independently substituted with one or more Z.sup.7 groups
and optionally substituted with one or more Z.sup.1 groups.
[0349] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is fused-heterocycle, wherein
fused-heterocycle is substituted with one or more Z.sup.7 groups
and optionally substituted with one or more Z.sup.1 groups.
[0350] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from bicyclic aryl, tricyclic
aryl, bicyclic heteroaryl, tricyclic heteroaryl bicyclic
fused-heterocycle and tricyclic fused-heterocycle, wherein bicyclic
aryl, tricyclic aryl, bicyclic heteroaryl, tricyclic heteroaryl
bicyclic fused-heterocycle and tricyclic fused-heterocycle are each
independently substituted with one or more Z.sup.7 groups and
optionally substituted with one or more Z.sup.1 groups.
[0351] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is selected from bicyclic
fused-heterocycle and tricyclic fused-heterocycle, wherein bicyclic
fused-heterocycle and tricyclic fused-heterocycle fused-heterocycle
are each substituted with one or more Z.sup.7 groups and optionally
substituted with one or more Z.sup.1 groups.
[0352] Another specific group of compounds of formula I are
compounds wherein R.sup.4 is tricyclic fused-heterocycle, wherein
tricyclic fused-heterocycle fused-heterocycle is substituted with
one or more Z.sup.7 groups and optionally substituted with one or
more Z.sup.1 groups.
[0353] A specific value for Z.sup.10 is: [0354] i) halo,
(C.sub.1-C.sub.6)haloalkyl; or [0355] ii) (C.sub.1-C.sub.6)alkyl
optionally substituted with --OH,
--O--(C.sub.1-C.sub.6)haloalkyl.
[0356] Another specific value for Z.sup.10 is halo.
[0357] Another specific value for R.sup.4 is:
##STR00033##
[0358] Another specific value for R.sup.4 is:
##STR00034##
[0359] Another specific value for R.sup.4 is:
##STR00035##
[0360] Another specific value for R.sup.4 is:
##STR00036##
[0361] Another specific value for R.sup.4 is:
##STR00037##
[0362] Another specific value for R.sup.4 is:
##STR00038##
[0363] Another specific value for R.sup.4 is:
##STR00039##
[0364] Another specific value for R.sup.4 is:
##STR00040##
[0365] Another specific value for R.sup.4 is:
##STR00041##
[0366] Another specific value for R.sup.4 is:
##STR00042##
[0367] Another specific value for R.sup.4 is:
##STR00043##
[0368] Another specific value for R.sup.4 is:
##STR00044##
[0369] Another specific value for R.sup.4 is:
##STR00045##
[0370] Another specific value for R.sup.4 is:
##STR00046##
[0371] Another specific value for R.sup.4 is:
##STR00047##
[0372] Another specific value for R.sup.4 is:
##STR00048##
[0373] Another specific value for R.sup.4 is:
##STR00049##
[0374] Another specific value for R.sup.4 is:
##STR00050##
[0375] Another specific value for R.sup.4 is:
##STR00051##
[0376] Another specific group of compounds of formula I are
compounds wherein the stereochemistry of the R.sup.4 substituent
relative to the carbon of formula Ito which it is attached is the
(R) stereochemistry.
[0377] Another specific group of compounds of formula I are
compounds wherein the stereochemistry of the R.sup.4 substituent
relative to the carbon of formula Ito which it is attached is the
(S) stereochemistry.
[0378] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0379] a) H, halo, (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0380] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, nitro, cyano, aryl, heterocycle and
heteroaryl, wherein any aryl, heterocycle or heteroaryl is
optionally substituted with one or more Z.sup.10 groups;
[0381] c) --C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11,
--O--R.sup.11, --S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)allyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups;
[0382] d) --N(R.sup.9)R.sup.10; --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups;
[0383] e)
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.-
13, --C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)allyl-Z.sup.13,
--(C.sub.1-C.sub.6)allyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)allyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloallyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alk.sub.Yl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle and heteroaryl, either
alone or as part of a group, is optionally substituted with one or
more Z.sup.1 groups;
[0384] f) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloallyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein any
--X(C.sub.1-C.sub.6)alkyl and --X(C.sub.1-C.sub.6)haloalkyl is
substituted with one or more Z.sup.3 groups and optionally
substituted with one or more Z.sup.1 groups, and wherein any
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle is substituted with one or more
Z.sup.4 groups and optionally substituted with one or more Z.sup.1
groups;
[0385] g) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups;
[0386] h) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle, wherein any aryl, heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups;
[0387] i) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups; and
[0388] j) --NR.sub.eR.sub.f, --C(O)NIZ.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NIZ.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein each
(C.sub.1-C.sub.6)alkyl is optionally substituted with one or more
Z.sup.1 groups.
[0389] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0390] a) H, (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0391] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, heterocycle and heteroaryl,
wherein any aryl, heterocycle or heteroaryl is optionally
substituted with one or more Z.sup.10 groups;
[0392] c) --C(.dbd.O)--O--R.sup.11, --O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups;
[0393] d) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10, wherein each R.sup.9 is
independently selected from H, (C.sub.1-C.sub.6)alkyl and
(C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups;
[0394] e) --(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle
and --(C.sub.2-C.sub.6)alkynyl-aryl, wherein
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle and
--(C.sub.2-C.sub.6)alkynyl-aryl are each optionally substituted
with one or more Z.sup.1 groups;
[0395] f) --X(C.sub.1-C.sub.6)alkyl, wherein
--X(C.sub.1-C.sub.6)alkyl is substituted with one or more Z.sup.3
groups and optionally substituted with one or more Z.sup.1 groups,
and wherein X is O;
[0396] g) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups;
[0397] h) aryl, heteroaryl and heterocycle, wherein aryl,
heteroaryl and heterocycle are each substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups;
[0398] i) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups; and
[0399] j) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f, wherein each
(C.sub.1-C.sub.6)alkyl is optionally substituted with one or more
Z.sup.1 groups.
[0400] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0401] a) H, (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0402] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, heterocycle and heteroaryl,
wherein any aryl, heterocycle or heteroaryl is optionally
substituted with one or more Z.sup.10 groups;
[0403] c) --C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11,
--O--R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups;
[0404] d) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10, wherein each R.sup.9 is
independently selected from H, (C.sub.1-C.sub.6)alkyl and
(C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups;
[0405] e) --(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle
and --(C.sub.2-C.sub.6)alkynyl-aryl, wherein
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle and
--(C.sub.2-C.sub.6)alkynyl-aryl are each optionally substituted
with one or more Z.sup.1 groups;
[0406] f) --X(C.sub.1-C.sub.6)alkyl, wherein
--X(C.sub.1-C.sub.6)alkyl is substituted with one or more Z.sup.3
groups and optionally substituted with one or more Z.sup.1 groups,
and wherein X is O;
[0407] g) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups;
[0408] h) aryl, heteroaryl and heterocycle, wherein aryl,
heteroaryl and heterocycle are each substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups;
[0409] i) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups; and
[0410] j) --NR.sub.eR.sub.f, --C(O)NIZ.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f, wherein each
(C.sub.1-C.sub.6)alkyl is optionally substituted with one or more
Z.sup.1 groups.
[0411] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0412] a) H, (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0413] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, heterocycle and heteroaryl,
wherein any aryl, heterocycle or heteroaryl is optionally
substituted with one or more Z.sup.10 groups;
[0414] c) --C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11,
--O--R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups;
[0415] d) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10, wherein each R.sup.9
is independently selected from H, (C.sub.1-C.sub.6)allyl and
(C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein any aryl, heterocycle or
heteroaryl is optionally substituted with one or more Z.sup.10
groups;
[0416] e) --(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle
and --(C.sub.2-C.sub.6)alkynyl-aryl, wherein
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle and
--(C.sub.2-C.sub.6)alkynyl-aryl are each optionally substituted
with one or more Z.sup.1 groups;
[0417] f) --X(C.sub.1-C.sub.6)alkyl, wherein
--X(C.sub.1-C.sub.6)alkyl is substituted with one or more Z.sup.3
groups and optionally substituted with one or more Z.sup.1 groups,
and wherein X is O; and
[0418] g) --NR.sub.eR.sub.f.
[0419] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0420] a) (C.sub.1-C.sub.6)haloalkyl; and
[0421] b) (C.sub.1-C.sub.6)haloalkyl, wherein
(C.sub.1-C.sub.6)haloalkyl is substituted with one or more Z.sup.6
groups and optionally substituted with one or more Z.sup.1
groups.
[0422] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0423] a) (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0424] b) (C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)cycloalkyl and
aryl, wherein any aryl is optionally substituted with one or more
Z.sup.10 groups;
[0425] c) --(C.sub.1-C.sub.6)alkyl-R.sup.11, wherein each R.sup.n
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl and aryl,
wherein aryl is optionally substituted with one or more Z.sup.10
groups;
[0426] d) --(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle
and --(C.sub.2-C.sub.6)alkynyl-aryl, wherein
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle and
--(C.sub.2-C.sub.6)alkynyl-aryl are each optionally substituted
with one or more Z.sup.1 groups;
[0427] e) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups;
[0428] f) aryl, wherein aryl is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups; and
[0429] g) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle
and (C.sub.2-C.sub.6)alkynyl, wherein (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups.
[0430] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0431] a) (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0432] b) (C.sub.2-C.sub.6)alkynyl and aryl, wherein any aryl is
optionally substituted with one or more Z.sup.10 groups;
[0433] c) --(C.sub.1-C.sub.6)alkyl-R.sup.n, wherein each R.sup.11
is independently selected from (C.sub.3-C.sub.7)cycloalkyl and
aryl, wherein any aryl is optionally substituted with one or more
Z.sup.10 groups;
[0434] d) --(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle
and --(C.sub.2-C.sub.6)alkynyl-aryl, wherein
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle and
--(C.sub.2-C.sub.6)alkynyl-aryl are each optionally substituted
with one or more Z.sup.1 groups;
[0435] e) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups;
[0436] f) aryl, wherein aryl is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups; and
[0437] g) (C.sub.1-C.sub.6)haloalkyl and (C.sub.2-C.sub.6)alkynyl,
wherein (C.sub.1-C.sub.6)haloalkyl and (C.sub.2-C.sub.6)alkynyl are
each substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups.
[0438] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0439] a) (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0440] b) (C.sub.2-C.sub.6)alkynyl and aryl, wherein any aryl is
optionally substituted with one or more Z.sup.10 groups;
[0441] c) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups; and
[0442] d) aryl, wherein aryl is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups.
[0443] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0444] a) (C.sub.1-C.sub.6)alkyl and (C.sub.1-C.sub.6)haloalkyl;
and
[0445] b) (C.sub.2-C.sub.6)alkynyl and aryl, wherein any aryl is
optionally substituted with one or more (C.sub.1-C.sub.6)alkyl
groups.
[0446] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from (C.sub.1-C.sub.6)alkyl,
C.sub.1-C.sub.6)haloalkyl and (C.sub.2-C.sub.6)alkynyl.
[0447] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0448] a)
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.-
13, --C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)allyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)allyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)allynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.a,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 and
-halo(C.sub.1-C.sub.6)allyl-Z.sup.3, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle and heteroaryl, either
alone or as part of a group, are each optionally substituted with
one or more Z.sup.1 groups;
[0449] b) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle, wherein --X(C.sub.1-C.sub.6)alkyl
and --X(C.sub.1-C.sub.6)haloalkyl are each substituted with one or
more Z.sup.3 groups and optionally substituted with one or more
Z.sup.1 groups, and wherein --X(C.sub.2-C.sub.6)alkenyl,
--X(C.sub.2-C.sub.6)alkynyl and --X(C.sub.3-C.sub.7)carbocycle are
each substituted with one or more Z.sup.4 groups and optionally
substituted with one or more Z.sup.1 groups;
[0450] c) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups;
[0451] d) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle, wherein any aryl, heteroaryl and heterocycle,
either alone or as part of a group, is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups;
[0452] e) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups; and
[0453] f) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)allylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f, wherein each
(C.sub.1-C.sub.6)alkyl is optionally substituted with one or more
Z.sup.1 groups.
[0454] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0455] a) --(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle
and --(C.sub.2-C.sub.6)alkynyl-aryl, wherein
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle and
--(C.sub.2-C.sub.6)alkynyl-aryl are each optionally substituted
with one or more Z.sup.1 groups;
[0456] b) --X(C.sub.1-C.sub.6)alkyl, wherein
--X(C.sub.1-C.sub.6)alkyl is substituted with one or more Z.sup.3
groups and optionally substituted with one or more Z.sup.1 groups,
and wherein X is O;
[0457] c) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups;
[0458] d) aryl, heteroaryl and heterocycle, wherein aryl,
heteroaryl and heterocycle are each substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups;
[0459] e) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups; and
[0460] f) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f, wherein
(C.sub.1-C.sub.6)alkyl is optionally substituted with one or more
Z.sup.1 groups.
[0461] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is (C.sub.1-C.sub.6)haloalkyl, wherein
(C.sub.1-C.sub.6)haloalkyl is substituted with one or more Z.sup.6
groups and optionally substituted with one or more Z.sup.1
groups.
[0462] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0463] a) --(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle
and --(C.sub.2-C.sub.6)alkynyl-aryl, wherein
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle and
--(C.sub.2-C.sub.6)alkynyl-aryl are each optionally substituted
with one or more Z.sup.1 groups;
[0464] b) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups;
[0465] c) aryl, wherein aryl is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups; and
[0466] d) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle
and (C.sub.2-C.sub.6)alkynyl, wherein (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups.
[0467] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0468] a) --(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle
and --(C.sub.2-C.sub.6)alkynyl-aryl, wherein
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle and
--(C.sub.2-C.sub.6)alkynyl-aryl are each optionally substituted
with one or more Z.sup.1 groups;
[0469] b) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups;
[0470] c) aryl, wherein aryl is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups; and
[0471] d) (C.sub.1-C.sub.6)haloalkyl and (C.sub.2-C.sub.6)alkynyl,
wherein (C.sub.1-C.sub.6)haloalkyl and (C.sub.2-C.sub.6)alkynyl are
each substituted with one or more Z.sup.6 groups and optionally
substituted with one or more Z.sup.1 groups.
[0472] Another specific group of compounds of formula I are
compounds wherein R.sup.7 is selected from:
[0473] a) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more Z.sup.1 groups; and
[0474] b) aryl, wherein aryl is substituted with one or more
Z.sup.5 groups and optionally substituted with one or more Z.sup.1
groups.
[0475] Another specific group of compounds of formula I are
compounds wherein R.sup.7a is selected from:
[0476] a) H, halo, (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0477] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, nitro, cyano, aryl, heterocycle and
heteroaryl;
[0478] c) --C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11,
--O--R.sup.11, --S--R.sup.11, --S(O)--R.sup.11,
--SO.sub.2--R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and
[0479] d) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl,
[0480] and wherein any aryl, heterocycle or heteroaryl of R.sup.7a
is optionally substituted with one or more (e.g. 1, 2 or 3)
Z.sup.10 groups, and wherein R.sup.7a is not OH.
[0481] Another specific group of compounds of formula I are
compounds wherein R.sup.7 has any of the above recited values for
R.sup.7 provided R.sup.7 is not OH.
[0482] Another specific value for R.sup.7 is:
##STR00052## ##STR00053## ##STR00054##
[0483] Another specific value for R.sup.7 is:
##STR00055## ##STR00056## ##STR00057##
[0484] Another specific value for R.sup.7 is:
##STR00058##
[0485] Another specific value for R.sup.7 is:
##STR00059##
[0486] Another specific value for R.sup.7 is:
##STR00060##
[0487] Another specific value for R.sup.7 is:
##STR00061##
[0488] Another specific group of compounds of formula In, Io, Ip
and Iq are compounds wherein W is a five-membered heteroaryl
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups.
[0489] Another specific group of compounds of formula In, Io, Ip
and Iq are compounds wherein W is imidazolyl, triazolyl, or
tetrazolyl each optionally substituted with one or more (e.g. 1, 2,
3, 4 or 5) Z.sup.1 groups.
[0490] A specific value for Z.sup.1 is --(C.sub.1-C.sub.6)allyl or
-aryl, wherein any (C.sub.1-C.sub.6)alkyl, or aryl of Z.sup.1 is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
halogen, --OH, --OR.sub.b, --CN, --NR.sub.aC(O).sub.2R.sub.b,
-heteroaryl, -heterocycle, --Oheteroaryl, --Oheterocycle,
--NHheteroaryl, --NHheterocycle, or
--S(O).sub.2NR.sub.cR.sub.d.
[0491] Another specific group of compounds of formula I are
compounds wherein R.sup.13a is selected from:
[0492] a) R.sup.11, --C(.dbd.O)--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)allyl-S--R.sup.n,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.n and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups; and
[0493] b) --C(.dbd.O)--N(R.sup.9)R.sup.10,
--SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups; provided R.sup.13a is not H.
[0494] Another specific group of compounds of formula I are
compounds wherein R.sup.13a is selected from:
[0495] a) R.sup.11, --C(.dbd.O)--R.sup.11,
--C(.dbd.O)--O--R.sup.11, --O--R.sup.11, --S(O)--R.sup.11,
--SO.sub.2--R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)allyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11, wherein each R.sup.11
is independently selected from (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups; and
[0496] b) --C(.dbd.O)--N(R.sup.9)R.sup.10,
--SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)allyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups.
[0497] Another specific group of compounds of formula I are
compounds wherein R.sup.13 is selected from:
[0498] a) R.sup.11 and --(C.sub.1-C.sub.6)alkyl-R.sup.11, wherein
each R.sup.11 is independently selected from
(C.sub.1-C.sub.6)all(yl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, heterocycle and heteroaryl,
wherein aryl, heterocycle and heteroaryl are each optionally
substituted with one or more (e.g. 1, 2 or 3) Z.sup.11 groups;
[0499] b) --(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups;
[0500] c) (C.sub.1-C.sub.6)alkyl, wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0501] d) aryl, heteroaryl, heterocycle, wherein aryl heteroaryl
and heterocycle are each independently substituted with one or more
(e.g. 1, 2, 3, 4 or 5) Z.sup.5 groups and optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0502] e) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.6 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups; and
[0503] f) --(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f, wherein
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f is optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups.
[0504] Another specific group of compounds of formula I are
compounds wherein R.sup.13 is selected from:
[0505] a) R.sup.11 and --(C.sub.1-C.sub.6)alkyl-R.sup.11, wherein
each R.sup.11 is independently selected from H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, heterocycle and heteroaryl,
wherein aryl, heterocycle and heteroaryl are each optionally
substituted with one or more (e.g. 1, 2 or 3) Z.sup.H groups;
[0506] b) --(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl, and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11, wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl, wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups;
[0507] c) (C.sub.1-C.sub.6)alicyl, wherein (C.sub.1-C.sub.6)alkyl
is substituted with one or more Z.sup.2 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z' groups;
[0508] d) aryl, heteroaryl, heterocycle, wherein aryl heteroaryl
and heterocycle are each independently substituted with one or more
(e.g. 1, 2, 3, 4 or 5) Z.sup.5 groups and optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0509] e) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl, wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.6 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups; and
[0510] f) --(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f, wherein each
(C.sub.1-C.sub.6)alkyl is optionally substituted with one or more
(e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups.
[0511] Another specific group of compounds of formula I are
compounds wherein R.sup.13 is selected from:
[0512] a) R.sup.11 and --(C.sub.1-C.sub.6)alkyl-R.sup.11, wherein
each R.sup.11 is independently selected from
(C.sub.1-C.sub.6)alkyl, aryl, heterocycle and heteroaryl, wherein
aryl, heterocycle and heteroaryl are each optionally substituted
with one or more (e.g. 1, 2 or 3) Z.sup.11 groups; and
[0513] b) --(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10, wherein each
R.sup.9 is independently selected from H and
(C.sub.1-C.sub.6)alkyl, and each R.sup.10 is independently selected
from R.sup.11, wherein each R.sup.11 is independently selected from
H, (C.sub.1-C.sub.6)alkyl and aryl, wherein aryl, is optionally
substituted with one or more (e.g. 1, 2 or 3) Z.sup.11 groups.
[0514] Another specific value for R.sup.13 is H.
[0515] Another specific value for R.sup.13 is:
##STR00062##
[0516] A specific group of compounds of formula I are compounds
wherein R.sub.g is independently selected from --OR.sub.a,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)carbocycle
(C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle and heteroaryl, wherein
any (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)carbocycle
--(C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle and heteroaryl of
R.sub.g is optionally substituted with one or more (e.g. 1, 2, 3, 4
or 5) Z.sup.1 groups.
[0517] In one embodiment, the invention provides a compound of the
invention which is a compound of formula I:
[0518] wherein:
[0519] G.sup.1 is N; G.sup.2 is CR.sup.8; and the dashed bond is a
double bond; or
[0520] G.sup.1 is CR.sup.5; G.sup.2 is N; and the dashed bond is a
double bond; or
[0521] G.sup.1 is CR.sup.5; G.sup.2 is NR.sup.13; the dashed bond
is a single bond; and R.sup.7 is an oxo (.dbd.O) group;
[0522] R.sup.2 is R.sup.2a or R.sup.2b;
[0523] R.sup.3 is R.sup.3a or R.sup.3b;
[0524] R.sup.3' is R.sup.3a' or R.sup.3b';
[0525] R.sup.4 is R.sup.4a or Rob;
[0526] R.sup.5 is R.sup.5a or R.sup.5b;
[0527] R.sup.6 is R.sup.6a or R.sup.6b;
[0528] R.sup.7 is R.sup.7a or R.sup.7b;
[0529] R.sup.8 is R.sup.8a or R.sup.8b;
[0530] R.sup.13 is R.sup.13a or R.sup.13b;
[0531] R.sup.1a is selected from:
[0532] a) H, halo, (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0533] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, nitro, cyano, aryl, heterocycle and
heteroaryl;
[0534] c) --C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11,
--O--R.sup.11, --S--R.sup.11, --S(O)--R.sup.11,
--SO.sub.2--R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11; wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and
[0535] d) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10; wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl; and
each R.sup.10 is independently selected from R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11, --SO.sub.2--R.sup.11,
--C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11 and
--C(.dbd.O)N(R.sup.9)R.sup.11; wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and
[0536] wherein any aryl, heterocycle or heteroaryl of R.sup.1a is
optionally substituted with one or more (e.g. 1, 2 or 3) Z.sup.10
groups;
[0537] R.sup.1b is selected from:
[0538] a)
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.6)carbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.-
7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alicyl-S--(C.sub.1-C.sub.6)allyl-Z.sup.13,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)allynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 or
-halo(C.sub.1-C.sub.6)allyl-Z.sup.3; wherein
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl or heteroaryl are each optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0539] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle; wherein Spiro-bicyclic carbocycle,
fused-bicyclic carbocycle or bridged-bicyclic carbocycle are
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a carbocycle or
heterocycle wherein the carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0540] c) (C.sub.1-C.sub.6)alkyl; wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0541] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle; wherein (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl are each substituted with one or more
Z.sup.3 groups and optionally substituted with one or more Z.sup.1
groups; and wherein (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl and (C.sub.3-C.sub.7)carbocycle are each
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups
and optionally substituted with one or more Z.sup.1 groups;
[0542] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle; wherein aryl heteroaryl and heterocycle are each
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.5 groups
and optionally substituted with one or more Z.sup.1 groups;
[0543] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl; wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.6 groups
and optionally substituted with one or more Z.sup.1 groups; and
[0544] g) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NIZ.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alicylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f; wherein each
(C.sub.1-C.sub.6)alkyl is substituted with one or more (e.g. 1, 2,
3, 4 or 5) Z.sup.6 groups and optionally substituted with one or
more Z.sup.1 groups;
[0545] R.sup.2a is selected from:
[0546] a) H, (C.sub.1-C.sub.6)alkyl and
--O(C.sub.1-C.sub.6)alkyl;
[0547] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle, heteroaryl, halo, nitro and cyano;
[0548] c) C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11,
--S--R.sup.11, --S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11; wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl and
heterocycle and heteroaryl; wherein aryl, heterocycle or heteroaryl
are each optionally substituted with one or more (e.g. 1, 2 or 3)
Z.sup.11 groups;
[0549] d) --OH, --O(C.sub.2-C.sub.6)alkenyl,
--O(C.sub.2-C.sub.6)alkynyl, --O(C.sub.1-C.sub.6)haloalkyl,
--O(C.sub.3-C.sub.7)cycloalkyl, --Oaryl, --Oheterocycle and
--Oheteroaryl; and
[0550] e) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10, and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10; wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl; and each R.sup.10 is independently
selected from R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--SO.sub.2--R.sup.11, --C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11
and --C(.dbd.O)N(R.sup.9)R.sup.11; wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl;
[0551] R.sup.26 is selected from:
[0552] a)
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.-
7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.elt.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 or
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3; wherein
(C.sub.1-C.sub.6)alkyl, --(C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl or heteroaryl are each optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0553] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,
fused-bicyclic carbocycle or bridged-bicyclic carbocycle are
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle wherein the
(C.sub.3-C.sub.6)carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0554] c) (C.sub.1-C.sub.6)alkyl; wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0555] d) --X(C.sub.1-C.sub.6)alkyl, X(C.sub.1-C.sub.6)haloalkyl,
X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle; wherein (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloallyl are each substituted with one or more
Z.sup.3 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups; and wherein (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl and (C.sub.3-C.sub.7)carbocycle are each
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups
and optionally substituted with one or more Z.sup.1 groups;
[0556] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle; wherein aryl heteroaryl and heterocycle are each
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.5 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0557] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl; wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.6 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; and
[0558] g) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f; wherein each
(C.sub.1-C.sub.6)alkyl is substituted with one or more (e.g. 1, 2,
3, 4 or 5) Z.sup.6 groups and optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0559] R.sup.3a is (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl,
--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl,
--(C.sub.1-C.sub.6)alkyl-aryl,
--(C.sub.1-C.sub.6)alkyl-heterocycle,
--(C.sub.1-C.sub.6)alkyl-heteroaryl, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.2-C.sub.6)alkenyl,
--O(C.sub.2-C.sub.6)alkynyl, --O(C.sub.3-C.sub.7)cycloalkyl,
--Oaryl, --O(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)cycloalkyl,
--O(C.sub.1-C.sub.6)alkyl-aryl,
--O(C.sub.1-C.sub.6)alkyl-heterocycle and
--O(C.sub.1-C.sub.6)alkyl-heteroaryl; wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl of R.sup.3' is
optionally substituted with one or more (e.g. 1, 2 or 3) groups
selected from --O(C.sub.1-C.sub.6)alkyl, halo, oxo and --CN; and
wherein any (C.sub.3-C.sub.7)cycloalkyl, aryl, heterocycle, or
heteroaryl of R.sup.1a is optionally substituted with one or more
(e.g. 1, 2 or 3) groups selected from (C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl, halo, oxo and --CN; and R.sup.3a' is
H;
[0560] R.sup.3b is --(C.sub.3-C.sub.7)carbocycle, aryl, heteroaryl,
heterocycle, --(C.sub.1-C.sub.6)alkylOH,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.2-C.sub.6)alkyl-O--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.2-C.sub.6)alkyl-S--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.2-C.sub.6)alkyl-S(O)--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.2-C.sub.6)alkenyl-Z.sup.12,
--(C.sub.2-C.sub.6)alkyl-SO.sub.2--(C.sub.2-C.sub.6)alkynyl-Z.sup.12,
--(C.sub.2-C.sub.6)alkyl-NR.sub.aR.sub.b,
--(C.sub.2-C.sub.6)alkylOC(O)--NR.sub.cR.sub.d,
--(C.sub.2-C.sub.6)alkyl-NR.sub.a--C(O)--OR.sub.b,
--(C.sub.2-C.sub.6)alkyl-NR.sub.a--C(O)--NR.sub.aR.sub.b,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.cR.sub.d,
--(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2Oaryl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.1-C.sub.6)alkyl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)alkenyl,
--(C.sub.1-C.sub.6)allyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)alkynyl,
--(C.sub.1-C.sub.6)allyl-NR.sub.a--SO.sub.2--(C.sub.3-C.sub.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.3-C.sub.7)carbocyc-
le, --(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-aryl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-heteroaryl,
--(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-heterocycle,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.aR.sub.b,
--O(C.sub.1-C.sub.6)alkylOC(O)--NR.sub.clt.sub.d,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--C(O)--OR.sub.b,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--C(O)--NR.sub.aR.sub.b,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)alkenyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.3-C.sub.7)carbocycle-
,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.3-C.sub.7)carboc-
ycle, --O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-aryl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-heteroaryl,
--O(C.sub.1-C.sub.6)allyl-NR.sub.a--SO.sub.2-heterocycle,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--NR.sub.aR.sub.b,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2--(C.sub.3-C.sub.7)carbocycle-
,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-halo(C.sub.3-C.sub.7)carboc-
ycle, --O(C.sub.1-C.sub.6)alkyl-NR.sub.a--SO.sub.2-aryl,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2NR.sub.cR.sub.3,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.1-C.sub.6)alkyl-NR.sub.aSO.sub.2Oaryl, --Oheteroaryl,
--Oheterocycle, --Sheteroaryl, --Sheterocycle, --S(O)heteroaryl,
--S(O)heterocycle, --SO.sub.2heteroaryl or --SO.sub.2heterocycle;
wherein any (C.sub.1-C.sub.6)alkyl, aryl,
(C.sub.3-C.sub.7)carbocycle, heteroaryl or heterocycle of R.sup.3b
is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; and R.sup.3b' is H, (C.sub.1-C.sub.6)alkyl or
--O(C.sub.1-C.sub.6)alkyl; or R.sup.3b and R.sup.3b' together with
the carbon to which they are attached form a heterocycle or
(C.sub.3-C.sub.7)carbocycle which heterocycle or
(C.sub.3-C.sub.7)carbocycle of R.sup.3b and R.sup.3b' together with
the carbon to which they are attached is optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0561] R.sup.4a is selected from aryl, heterocycle and heteroaryl,
wherein any aryl, heterocycle and heteroaryl of R.sup.4a is
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
groups each independently selected from halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, --OH,
--O(C.sub.1-C.sub.6)alkyl, --SH, --S(C.sub.1-C.sub.6)alkyl,
--NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl and
--N((C.sub.1-C.sub.6)alkyl).sub.2; wherein (C.sub.1-C.sub.6)alkyl
is optionally substituted with hydroxy, --O(C.sub.1-C.sub.6)alkyl,
cyano or oxo;
[0562] R.sup.4b is selected from:
[0563] a) (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl and
(C.sub.2-C.sub.6)alkynyl; wherein (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl are each
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0564] b) (C.sub.3-C.sub.14)carbocycle; wherein
(C.sub.3-C.sub.14)carbocycle is optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups; wherein two Z.sup.1
groups together with the atom or atoms to which they are attached
optionally form a (C.sub.3-C.sub.7)carbocycle or heterocycle;
[0565] c) Spiro-heterocycle or bridged-heterocycle; wherein
Spiro-heterocycle or bridged-heterocycle is optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups; or wherein
two Z.sup.1 groups together with the atom or atoms to which they
are attached optionally form a (C.sub.3-C.sub.7)carbocycle or
heterocycle; and
[0566] d) aryl, heteroaryl, spiro-, fused-, or bridged-heterocycle;
wherein aryl, heteroaryl, or spiro-, fused-, or bridged-heterocycle
are each independently substituted with one or more Z.sup.7 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; or
[0567] R.sup.4 and R.sup.3 together with the atoms to which they
are attached form a macroheterocycle or a macrocarbocycle wherein
any macroheterocycle or macrocarbocycle of R.sup.4 and R.sup.3
together with the atoms to which they are attached may be
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; and R.sup.3b' is H or (C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)allyl.
[0568] R.sup.5a is selected from:
[0569] a) halo, nitro and cyano;
[0570] b) R.sup.11, --C(.dbd.O)--R.sup.11,
--C(.dbd.O)--O--R.sup.11, --O--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alicyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11, O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11; wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)allynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups;
[0571] c) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10, and
--(C.sub.1-C.sub.6)allyl-SO.sub.2--N(R.sup.9)R.sup.10; wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl; and
each R.sup.10 is independently selected from R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11, --SO.sub.2--R.sup.11,
--C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11 and
--C(.dbd.O)N(R.sup.9)R.sup.11; wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl;
[0572] R.sup.5b is selected from:
[0573] a)
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)allyl-(C.sub.3-C.su-
b.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkylS(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub-
.6)carbocycle,
--(C.sub.1-C.sub.6)alkylSO.sub.2(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)c-
arbocycle, --(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)allynyl(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 or
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3; wherein
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl or heteroaryl are each optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0574] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,
fused-bicyclic carbocycle or bridged-bicyclic carbocycle are
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle wherein the
(C.sub.3-C.sub.7)carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0575] c) (C.sub.1-C.sub.6)alkyl; wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0576] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle; wherein (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)haloalkyl are each substituted with one or more
Z.sup.3 groups and optionally substituted with one or more Z.sup.1
groups; and wherein (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl and (C.sub.3-C.sub.7)carbocycle are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.4 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups;
[0577] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle; wherein aryl heteroaryl are heterocycle are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.5 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups;
[0578] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl; where
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.6 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups; and
[0579] g) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f; wherein each
(C.sub.1-C.sub.6)alkyl is independently substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.6 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0580] R.sup.6a is selected from:
[0581] a) H, halo, (C.sub.1-C.sub.6)alkyl, and
(C.sub.1-C.sub.6)haloalkyl
[0582] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, nitro, cyano, aryl, heterocycle or
heteroaryl;
[0583] c) --C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11,
--O--R.sup.11, --S--R.sup.11, --S(O)--R.sup.11,
--SO.sub.2--R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11; wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and
[0584] d) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.16,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.16; wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl; and
each R.sup.10 is independently selected from R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11, --SO.sub.2--R.sup.11,
--C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11 and
--C(.dbd.O)N(R.sup.9)R.sup.11; wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and
[0585] wherein any aryl, heterocycle or heteroaryl of R.sup.1a is
optionally substituted with one or more (e.g. 1, 2 or 3) Z.sup.10
groups;
[0586] R.sup.6b is selected from:
[0587] a)
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.su-
b.7)carbocycle, --(C.sub.1-C.sub.6)alkyl-S--(C
C.sub.6)alkyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
-halo(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 or
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3; wherein
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl or heteroaryl are optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0588] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,
fused-bicyclic carbocycle or bridged-bicyclic carbocycle are
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a carbocycle or
heterocycle wherein the carbocycle or heterocycle is optionally
substituted with one or more Z.sup.1 groups;
[0589] c) (C.sub.1-C.sub.6)allyl; wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.2 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0590] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle; wherein (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)haloalkyl are each independently substituted with
one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.3 groups and optionally
substituted with one or more Z.sup.1 groups; and wherein
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl and
(C.sub.3-C.sub.7)carbocycle are each independently substituted with
one or more Z.sup.4 groups and optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0591] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle wherein aryl heteroaryl and heterocycle are each
independently substituted with one or more Z.sup.5 groups and
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0592] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, and (C.sub.2-C.sub.6)alkynyl; wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and
[0593] (C.sub.2-C.sub.6)alkynyl are each independently substituted
with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.6 groups and
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; and
[0594] g) --NR.times.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NIZ.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NRA.sub.f; wherein each
(C.sub.1-C.sub.6)alkyl is independently substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.6 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0595] R.sup.7a is selected from:
[0596] a) H, halo, (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl;
[0597] b) (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)cycloalkyl, nitro, cyano, aryl, heterocycle and
heteroaryl;
[0598] c) --C(.dbd.O)--R.sup.11, --C(.dbd.O)--O--R.sup.11,
--O--R.sup.11, --S--R.sup.11, --S(O)--R.sup.11,
--SO.sub.2--R.sup.11, --(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)allyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.-
11 and --(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11; wherein each
R.sup.11 is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and
[0599] d) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10; wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl; and
each R.sup.10 is independently selected from R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11, --SO.sub.2--R.sup.11,
--C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11 and
--C(.dbd.O)N(R.sup.9)R.sup.11; wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; and
[0600] wherein any aryl, heterocycle or heteroaryl of R.sup.1a is
optionally substituted with one or more (e.g. 1, 2 or 3) Z.sup.19
groups;
[0601] R.sup.7b is selected from:
[0602] a)
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)allyl-Z.sup.-
13, --C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 or
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3; wherein
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl or heteroaryl are each optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0603] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,
fused-bicyclic carbocycle or bridged-bicyclic carbocycle are
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle wherein the
(C.sub.3-C.sub.6)carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0604] c) (C.sub.1-C.sub.6)alkyl; wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0605] d) --X(C.sub.1-C.sub.6)alkyl, X(C.sub.1-C.sub.6)haloalkyl,
X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle; wherein (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl are each substituted with one or more
Z.sup.3 groups and optionally substituted with one or more Z.sup.1
groups; and wherein (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl and (C.sub.3-C.sub.7)carbocycle are each
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups
and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups;
[0606] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle; wherein aryl, heteroaryl and heterocycle are each
substituted with one or more Z.sup.5 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0607] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl; wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
substituted with one or more Z.sup.6 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
and
[0608] g) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NRA.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)allylC(O)--NIZ.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f; wherein each
(C.sub.1-C.sub.6)alkyl is substituted with one or more (e.g. 1, 2,
3, 4 or 5) Z.sup.6 groups and optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups;
[0609] R.sup.8a is selected from:
[0610] a) halo, nitro and cyano;
[0611] b) R.sup.11, --C(.dbd.O)--R.sup.11,
--C(.dbd.O)--O--R.sup.11, --O--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11, O--R.sup.11,
--(C.sub.1-C.sub.6)allyl-S--R.sup.11,
--(C.sub.1-C.sub.6)allyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11; wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups;
[0612] c) --N(R.sup.9)R.sup.10, --C(.dbd.O)--N(R.sup.9)R.sup.10,
--O--C(.dbd.O)--N(R.sup.9)R.sup.10, --SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)allyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10; wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl; and
each R.sup.10 is independently selected from R.sup.11,
--(C.sub.1-C.sub.6)allyl-R.sup.11, --SO.sub.2--R.sup.11,
--C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11 and
--C(.dbd.O)N(R.sup.9)R.sup.11; wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl;
[0613] R.sup.8b is selected from:
[0614] a)
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.-
13, --C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alicyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)allyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7-
)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
-halo(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2NR.sub.cit.sub.a,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 or
-halo(C.sub.1-C.sub.6)alkyl-Z.sup.3; wherein
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl or heteroaryl are each optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups:
[0615] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,
fused-bicyclic carbocycle or bridged-bicyclic carbocycle are
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle wherein the
(C.sub.3-C.sub.7)carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0616] c) (C.sub.1-C.sub.6)alkyl; wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0617] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle; wherein (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl are each independently substituted with
one or more Z.sup.3 groups and optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups; and wherein any
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl and
(C.sub.3-C.sub.7)carbocycle are each independently substituted with
one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0618] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle wherein any aryl heteroaryl and heterocycle are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.5 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups;
[0619] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl; wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.6 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups; and
[0620] g) --NR.sub.eR.sub.f, --C(O)NR.sub.eR.sub.f,
--OC(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)allyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.r; wherein each
(C.sub.1-C.sub.6)alkyl is independently substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.6 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0621] R.sup.13a is selected from:
[0622] a) R.sup.11, --C(.dbd.O)--R.sup.11,
--C(.dbd.O)--O--R.sup.11, --O--R.sup.11, --S--R.sup.11,
--S(O)--R.sup.11, --SO.sub.2--R.sup.11,
--(C.sub.1-C.sub.6)allyl-R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-O--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S--R.sup.11,
--(C.sub.1-C.sub.6)alkyl-S(O)--R.sup.11 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--R.sup.11; wherein each R.sup.11
is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloallyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl; wherein aryl, heterocycle and
heteroaryl are each optionally substituted with one or more (e.g.
1, 2 or 3) Z.sup.11 groups; and
[0623] b) --C(.dbd.O)--N(R.sup.9)R.sup.10,
--SO.sub.2--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-C(.dbd.O)--N(R.sup.9)R.sup.10,
--(C.sub.1-C.sub.6)alkyl-O--C(.dbd.O)--N(R.sup.9)R.sup.10 and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--N(R.sup.9)R.sup.10; wherein each
R.sup.9 is independently selected from H, (C.sub.1-C.sub.6)alkyl
and (C.sub.3-C.sub.7)cycloalkyl; and each R.sup.10 is independently
selected from R.sup.11, --SO.sub.2--R.sup.11,
--C(.dbd.O)--R.sup.11, --C(.dbd.O)OR.sup.11 and
--C(.dbd.O)N(R.sup.9)R.sup.11; wherein each R.sup.11 is
independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl,
heterocycle and heteroaryl;
[0624] R.sup.13b is selected from:
[0625] a)
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.-
13, --C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--S--(C.sub.1-C.sub.6)allyl-Z.sup.13,
--S(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-Z.sup.14,
--(C.sub.1-C.sub.6)alkyl-C(O)--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-C(O)--O(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alkyl-Z.sup.13,
--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl-(C.sub.3-C.sub.7)carbo-
cycle,
--(C.sub.1-C.sub.6)alkyl-S--(C.sub.1-C.sub.6)alicyl-(C.sub.3-C.sub.-
7)carbocycle,
--(C.sub.1-C.sub.6)alkyl-S(O)--(C.sub.1-C.sub.6)allyl-(C.sub.3-C.sub.7)ca-
rbocycle,
--(C.sub.1-C.sub.6)alkyl-SO.sub.2--(C.sub.1-C.sub.6)alkyl-(C.sub-
.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.1-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.1-C.sub.6)haloalkyl,
-halo(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkenyl-aryl,
--(C.sub.2-C.sub.6)alkenyl-heteroaryl,
--(C.sub.2-C.sub.6)alkenyl-heterocycle,
--(C.sub.2-C.sub.6)alkynyl-(C.sub.3-C.sub.7)carbocycle,
--(C.sub.2-C.sub.6)alkynyl-aryl,
--(C.sub.2-C.sub.6)alkynyl-heteroaryl,
--(C.sub.2-C.sub.6)alkynyl-heterocycle,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.1 or
-halo(C.sub.1-C.sub.6)allyl-Z.sup.3,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl; wherein (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, aryl or
heteroaryl are each optionally substituted with one or more (e.g.
1, 2, 3, 4 or 5) Z.sup.1 groups:
[0626] b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and
bridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,
fused-bicyclic carbocycle or bridged-bicyclic carbocycle are
optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.1 groups; wherein two Z.sup.1 groups together with the atom
or atoms to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or heterocycle wherein the
(C.sub.3-C.sub.7)carbocycle or heterocycle is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0627] c) (C.sub.1-C.sub.6)allyl; wherein (C.sub.1-C.sub.6)alkyl is
substituted with one or more Z.sup.2 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0628] d) --X(C.sub.1-C.sub.6)alkyl, --X(C.sub.1-C.sub.6)haloalkyl,
--X(C.sub.2-C.sub.6)alkenyl, --X(C.sub.2-C.sub.6)alkynyl and
--X(C.sub.3-C.sub.7)carbocycle; wherein (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)haloalkyl are each independently substituted with
one or more Z.sup.3 groups and optionally substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.1 groups; and wherein any
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl and
(C.sub.3-C.sub.7)carbocycle are each independently substituted with
one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.4 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0629] e) aryl, heteroaryl, heterocycle, --Xaryl, --Xheteroaryl and
--Xheterocycle wherein any aryl heteroaryl and heterocycle are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.5 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups;
[0630] f) (C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl; wherein
(C.sub.1-C.sub.6)haloalkyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.2-C.sub.6)alkenyl and (C.sub.2-C.sub.6)alkynyl are each
independently substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z.sup.6 groups and optionally substituted with one or more (e.g. 1,
2, 3, 4 or 5) Z.sup.1 groups; and
[0631] g) --C(O)NR.sub.eR.sub.f, --SO.sub.2NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkylC(O)--NR.sub.eR.sub.f,
--(C.sub.1-C.sub.6)alkyl-O--C(O)--NR.sub.eR.sub.f and
--(C.sub.1-C.sub.6)alkyl-SO.sub.2NR.sub.eR.sub.f; wherein each
(C.sub.1-C.sub.6)alkyl is independently substituted with one or
more (e.g. 1, 2, 3, 4 or 5) Z.sup.6 groups and optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z.sup.1
groups;
[0632] or any of R.sup.5a and R.sup.6a, R.sup.6a and R.sup.7a,
R.sup.7a and R.sup.8a, R.sup.1 and R.sup.8, R.sup.1 and R.sup.2 or
R.sup.1 and R.sup.13 together with the atoms to which they are
attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or
7-membered heterocycle; wherein the 5 or 6-membered carbocycle or a
4, 5, 6 or 7-membered heterocycle is optionally substituted with
one or more (e.g. 1, 2 or 3) substituents each independently
selected from halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)cycloalkyl, --OH, --O(C.sub.1-C.sub.6)alkyl, --SH,
--S(C.sub.1-C.sub.6)allyl, --NH.sub.2, --NH(C.sub.1-C.sub.6)alkyl
and --N((C.sub.1-C.sub.6)alkyl).sub.2;
[0633] or any of R.sup.5 and R.sup.6, R.sup.6 and R.sup.7 or
R.sup.7 and R.sup.8, together with the atoms to which they are
attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or
7-membered heterocycle; wherein the 5 or 6-membered carbocycle or a
4, 5, 6 or 7-membered heterocycle are each independently
substituted with one or more (e.g. 1, 2 or 3) Z.sup.7 or Z.sup.8
groups; wherein when two Z.sup.7 groups are on same atom the two
Z.sup.7 groups together with the atom to which they are attached
optionally form a (C.sub.3-C.sub.7)carbocycle or 4, 5 or 6-membered
heterocycle;
[0634] or any of Wand R.sup.8, R.sup.1 and R.sup.2 or R.sup.1 and
R.sup.13 together with the atoms to which they are attached form a
5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle;
wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered
heterocycle are each independently substituted with one or more
(e.g. 1, 2 or 3) Z.sup.7 or Z.sup.8 groups; wherein when two
Z.sup.7 groups are on same atom the two Z.sup.7 groups together
with the atom to which they are attached optionally form a
(C.sub.3-C.sub.7)carbocycle or 4, 5 or 6-membered heterocycle;
[0635] X is independently selected from O, --C(O)--, --C(O)O--,
--S--, --S(O)--, --SO.sub.2--, --(C.sub.1-C.sub.6)alkylO--,
--(C.sub.1-C.sub.6)alkylC(O)--, --(C.sub.1-C.sub.6)alkylC(O)O--,
--(C.sub.1-C.sub.6)alkylS--, --(C.sub.1-C.sub.6)alkylS(O)--,
--(C.sub.1-C.sub.6)alkylSO.sub.2--;
[0636] each Z.sup.1 is independently selected from halo,
--NO.sub.2, --OH, .dbd.NOR.sub.a, --SH, --CN,
--(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, --(C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)carbocycle, --(C.sub.3-C.sub.7)halocarbocycle,
-aryl, -heteroaryl, -heterocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.2-C.sub.6)alkenyl, --O(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --Oaryl, --Oheteroaryl,
--Oheterocycle, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.2-C.sub.6)alkenyl, --S(C.sub.2-C.sub.6)alkynyl,
--S(C.sub.1-C.sub.6)haloalkyl, --S(C.sub.3-C.sub.7)carbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle, --Saryl, --Sheteroaryl,
--Sheterocycle, --S(O)(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.2-C.sub.6)alkenyl, --S(O)(C.sub.2-C.sub.6)alkynyl,
--S(O)(C.sub.1-C.sub.6)haloalkyl, --S(O)
(C.sub.3-C.sub.7)carbocycle, --S(O)(C.sub.3-C.sub.7)halocarbocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl, --S(O)aryl, --S(O)carbocycle,
--S(O)heteroaryl, --S(O)heterocycle,
--SO.sub.2(C.sub.2-C.sub.6)alkenyl,
--SO.sub.2(C.sub.2-C.sub.6)alkynyl,
--SO.sub.2(C.sub.1-C.sub.6)haloalkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.cR.sub.d,
--NR.sub.aC(O)R.sub.a, --NR.sub.aC(O)OR.sub.a,
--NR.sub.aC(O)NR.sub.cR.sub.d--NR.sub.aSO.sub.2R.sub.b,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --OS(O).sub.2R.sub.a, --C(O)R.sub.a,
--C(O)OR.sub.b, --C(O)NR.sub.cR.sub.d, and --OC(O)NR.sub.cR.sub.d,
wherein any (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --(C.sub.3-C.sub.7)halocarbocycle,
(C.sub.3-C.sub.7)carbocycle, (C.sub.3-C.sub.7)halocarbocycle, aryl,
heteroaryl or heterocycle of Z.sup.1 is optionally substituted with
one or more (e.g. 1, 2, 3, 4 or 5) halogen, --OH, --OR.sub.b, --CN,
--NR.sub.aC(O).sub.2R.sub.b, -heteroaryl, -heterocycle,
--Oheteroaryl, --Oheterocycle, --NHheteroaryl, --NHheterocycle, or
--S(O).sub.2NR.sub.cR.sub.d;
[0637] each Z.sup.2 is independently selected from --NO.sub.2,
--CN, spiro-heterocycle, bridge-heterocycle, spiro-bicyclic
carbocycle, bridged-bicyclic carbocycle,
NR.sub.aSO.sub.2(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2aryl, --NR.sub.aSO.sub.2heteroaryl,
--NR.sub.aSO.sub.2NR.sub.cR.sub.a,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl;
[0638] each Z.sup.3 is independently selected from --NO.sub.2,
--CN, --OH, oxo, .dbd.NOR.sub.a, thioxo, -aryl, -heterocycle,
-heteroaryl, --(C.sub.3-C.sub.7)halocarbocycle,
--O(C.sub.1-C.sub.6)alkyl, --O(C.sub.3-C.sub.7)carbocycle,
--Ohalo(C.sub.3-C.sub.7)carbocycle, --Oaryl, --Oheterocycle,
--Oheteroaryl, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --S(C.sub.3-C.sub.7)halocarbocycle,
--Saryl, --Sheterocycle, --Sheteroaryl,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O) (C.sub.3-C.sub.7)halocarbocycle, --S(O)aryl,
--S(O)heterocycle, --S(O)heteroaryl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, SO.sub.2aryl,
--SO.sub.2heterocycle, --SO.sub.2heteroaryl, --NR.sub.aR.sub.b,
--NR.sub.aC(O)R.sub.b, --C(O)NR.sub.cR.sub.d,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl;
[0639] each Z.sup.4 is independently selected from halogen,
--(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)carbocycle,
-halo(C.sub.1-C.sub.6)alkyl, --NO.sub.2, --CN, --OH, oxo,
.dbd.NOR.sub.a, thioxo, -aryl, -heterocycle, -heteroaryl,
--(C.sub.3-C.sub.7)halocarbocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.3-C.sub.7)carbocycle, --O(C.sub.3-C.sub.7)halocarbocycle,
--Oaryl, --Oheterocycle, --Oheteroaryl, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --S(C.sub.3-C.sub.7)halocarbocycle,
--Saryl, --Sheterocycle, --Sheteroaryl,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle, --S(O)aryl,
--S(O)heterocycle, --S(O)heteroaryl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, SO.sub.2aryl,
--SO.sub.2heterocycle, --SO.sub.2heteroaryl, --NR.sub.aR.sub.b,
--NR.sub.aC(O)R.sub.a, --C(O)NR.sub.cR.sup.d,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl;
[0640] each Z.sup.5 is independently selected from --NO.sub.2,
--CN, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --NR.sub.aSO.sub.2(C.sub.1-C.sub.6)alkyl,
--NR.sub.aSO.sub.2(C.sub.2-C.sub.6)alkenyl,
--NR.sub.aSO.sub.2(C.sub.2-C.sub.6)alkynyl,
--NR.sub.aSO.sub.2(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2aryl, --NR.sub.aSO.sub.2heteraryl,
--NR.sub.aSO.sub.2heteroaryl, --NR.sub.aSO.sub.2heterocycle,
--NR.sub.aC(O)alkyl, --NR.sub.aC(O)alkenyl, --NR.sub.aC(O)alkynyl,
--NR.sub.aC(O) (C.sub.3-C.sub.7)carbocycle,
--NR.sub.aC(O)(C.sub.3-C.sub.7)halocarbocycle, --NR.sub.aC(O)aryl,
--NR.sub.aC(O)heteroaryl, --NR.sub.aC(O)heterocycle,
NR.sub.aC(O)NR.sub.cR.sub.d and NR.sub.aC(O)OR.sub.b;
[0641] each Z.sup.6 is independently selected from --NO.sub.2,
--CN, --NR.sub.aR.sub.a, NR.sub.aC(O)R.sub.b,
--C(O)NR.sub.cR.sub.d, --(C.sub.3-C.sub.7)halocarbocycle, -aryl,
-heteroaryl, -heterocycle, --Oaryl, --Oheteroaryl, -Oheterocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.3-C.sub.7)carbocycle, --Ohalo(C.sub.1-C.sub.6)alkyl,
--Saryl, --Sheteroaryl, --Sheterocycle,
--S(C.sub.3-C.sub.7)halocarbocycle, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --S(C.sub.1-C.sub.6)haloalkyl,
--S(O)aryl, --S(O)heteroaryl, --S(O)heterocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)halo(C.sub.1-C.sub.6)alkyl, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2halo(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--SO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2aryl, --NR.sub.aSO.sub.2heteraryl,
--NR.sub.aSO.sub.2heteroaryl, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl;
[0642] each Z.sup.7 is independently selected from --NO.sub.2,
.dbd.NOR.sub.a, --CN, --(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--(C.sub.2-C.sub.6)alkenyl-Z.sup.12, --(C.sub.2-C.sub.6)alkenylOH,
--(C.sub.2-C.sub.6)alkynyl-Z.sup.12, --(C.sub.2-C.sub.6)alkynyl-OH,
--(C.sub.1-C.sub.6)haloalkyl-Z.sup.12,
--(C.sub.1-C.sub.6)haloalkylOH,
--(C.sub.3-C.sub.7)carbocycle-Z.sup.12,
--(C.sub.3-C.sub.7)carbocycle, OH,
--(C.sub.3-C.sub.7)halocarbocycle,
--(C.sub.1-C.sub.6)alkylNR.sub.cR.sub.d,
--(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, -aryl,
-heteroaryl, -heterocycle, --O(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--O(C.sub.2-C.sub.6)alkenyl, --O(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --Oaryl,
--O(C.sub.1-C.sub.6)allylNIZ.sub.eR.sub.d,
--O(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--O(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, --Oheteroaryl,
--Oheterocycle, --S(C.sub.1-C.sub.6)alkyl-Z.sup.12,
--S(C.sub.2-C.sub.6)alkenyl, --S(C.sub.2-C.sub.6)alkynyl,
--S(C.sub.1-C.sub.6)haloalkyl, --S(C.sub.3-C.sub.7)carbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle,
--S(C.sub.1-C.sub.6)alkylNIZ.sub.eR.sub.d,
--S(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--S(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, --Saryl,
--Sheteroaryl, --Sheterocycle, --S(O)(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.2-C.sub.6)alkenyl, --S(O)(C.sub.2-C.sub.6)alkynyl,
--S(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.1-C.sub.6)alkylNR.sub.cR.sub.d,
--S(O)(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--S(O)(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a, --S(O)aryl,
--S(O)heteroaryl, --S(O)heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.2-C.sub.6)alkenyl,
--SO.sub.2(C.sub.2-C.sub.6)alkynyl,
--SO.sub.2(C.sub.1-C.sub.6)haloalkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkylNR.sub.cR.sub.d,
--SO.sub.2(C.sub.1-C.sub.6)alkylNR.sub.aC(O)R.sub.a,
--SO.sub.2(C.sub.1-C.sub.6)alkylNR.sub.aSO.sub.2R.sub.a,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.aC(O)OR.sub.b,
--NR.sub.aC(O)NR.sub.cR.sub.d--NR.sub.aSO.sub.2R.sub.b,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --OS(O).sub.2R.sub.a,
--C(O)NR.sub.cR.sub.d, and --OC(O)NR.sub.cR.sub.d, wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle,
(C.sub.3-C.sub.7)halocarbocycle, aryl, heteroaryl or heterocycle of
Z.sup.7 is optionally substituted with one or more (e.g. 1, 2, 3, 4
or 5) halogen, --OH, --OR.sub.b, --CN, --NR.sub.aC(O).sub.2R.sub.b,
-heteroaryl, -heterocycle, --Oheteroaryl, --Oheterocycle,
--NHheteroaryl, --NHheterocycle, or
--S(O).sub.2NR.sub.cR.sub.d;
[0643] each Z.sup.8 is independently selected from --NO.sub.2 or
--CN;
[0644] each Z.sup.9 is independently selected from
--(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl;
[0645] each Z.sup.10 is independently selected from [0646] i) halo,
oxo, thioxo, (C.sub.2-C.sub.6)alkenyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.3-C.sub.7)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl-(C.sub.1-C.sub.6)alkyl-, --OH,
--O(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)haloallyl, --SH,
--S(C.sub.1-C.sub.6)alkyl, --SO(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl, --NH.sub.2,
--NH(C.sub.1-C.sub.6)alkyl and --N((C.sub.1-C.sub.6)alkyl).sub.2;
[0647] ii) (C.sub.1-C.sub.6)alkyl optionally substituted with --OH,
--O--(C.sub.1-C.sub.6)haloalkyl, or --O--(C.sub.1-C.sub.6)alkyl;
and [0648] iii) aryl, heterocycle and heteroaryl, which aryl,
heterocycle and heteroaryl is optionally substituted with halo,
(C.sub.1-C.sub.6)alkyl or COOH;
[0649] each Z.sup.11 is independently selected from Z.sup.10,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--NH(C.sub.1-C.sub.4)alkyl,
--C(.dbd.O)--N((C.sub.1-C.sub.4)alkyl).sub.2, --C(.dbd.O)-aryl,
--C(.dbd.O)-heterocycle and --C(.dbd.O)-heteroaryl;
[0650] each Z.sup.12 is independently selected from --NO.sub.2,
.dbd.NOR.sub.a, thioxo, -aryl, -heterocycle, -heteroaryl,
--(C.sub.3-C.sub.7)halocarbocycle, --(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)carbocycle, --Ohalo(C.sub.3-C.sub.7)carbocycle,
--Oaryl, --Oheterocycle, --Oheteroaryl, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.3-C.sub.7)carbocycle, --Shalo(C.sub.3-C.sub.7)carbocycle,
--Saryl, --Sheterocycle, --Sheteroaryl,
--S(O)(C.sub.1-C.sub.6)alkyl, --S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)halo(C.sub.3-C.sub.7)carbocycle, --S(O)aryl,
--S(O)heterocycle, --S(O)heteroaryl,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, SO.sub.2aryl,
--SO.sub.2heterocycle, --SO.sub.2heteroaryl, --NR.sub.aR.sub.a,
--NR.sub.aC(O)R.sub.b, --C(O)NR.sub.cR.sub.d,
--SO.sub.2NR.sub.elt.sub.d, --NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle and
--NR.sub.aSO.sub.2Oaryl;
[0651] each Z.sup.13 is independently selected from --NO.sub.2,
--OH, .dbd.NOR.sub.a, --SH, --CN,
--(C.sub.3-C.sub.7)halocarbocycle, --O(C.sub.1-C.sub.6)alkyl,
--O(C.sub.2-C.sub.6)alkenyl, --O(C.sub.2-C.sub.6)alkynyl,
--O(C.sub.1-C.sub.6)haloalkyl, --O(C.sub.3-C.sub.7)carbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle, --Oaryl, --Oheteroaryl,
--Oheterocycle, --S(C.sub.1-C.sub.6)alkyl,
--S(C.sub.2-C.sub.6)alkenyl, --S(C.sub.2-C.sub.6)alkynyl,
--S(C.sub.1-C.sub.6)haloalkyl, --S(C.sub.3-C.sub.7)carbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle, --Saryl, --Sheteroaryl,
--Sheterocycle, --S(O)(C.sub.1-C.sub.6)alkyl,
--S(O)(C.sub.2-C.sub.6)alkenyl,
--S(O)(C.sub.2-C.sub.6)alk.sub.ynyl,
--S(O)(C.sub.1-C.sub.6)haloalkyl,
--S(O)(C.sub.3-C.sub.7)carbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle, --S(O)aryl,
--S(O)heteroaryl, --S(O)heterocycle,
--SO.sub.2(C.sub.1-C.sub.6)alkyl,
--SO.sub.2(C.sub.2-C.sub.6)alkenyl,
--SO.sub.2(C.sub.2-C.sub.6)alkynyl,
--SO.sub.2(C.sub.1-C.sub.6)haloalkyl,
--SO.sub.2(C.sub.3-C.sub.7)carbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle, --SO.sub.2aryl,
--SO.sub.2heteroaryl, --SO.sub.2heterocycle,
--SO.sub.2NR.sub.cR.sub.d, --NR.sub.cR.sub.a,
--NR.sub.aC(O)R.sub.a, --NR.sub.aC(O)OR.sub.b,
--NR.sub.aC(O)NIZ.sub.eR.sub.d--NR.sub.aSO.sub.2R.sub.b,
--NR.sub.aSO.sub.2NR.sub.cR.sub.d,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --OS(O).sub.2R.sub.a, --C(O)R.sub.a,
--C(O)OR.sub.b, --C(O)NR.sub.cR.sub.d, and --OC(O)NR.sub.elt.sub.d;
wherein any (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --(C.sub.3-C.sub.7)halocarbocycle,
(C.sub.3-C.sub.7)carbocycle, (C.sub.3-C.sub.7)halocarbocycle, aryl,
heteroaryl or heterocycle of Z.sup.13 is optionally substituted
with one or more (e.g. 1, 2, 3, 4 or 5) halogen, --OH, --OR.sub.b,
--CN, --NR.sub.aC(O).sub.2R.sub.b, -heteroaryl, -heterocycle,
--Oheteroaryl, --Oheterocycle, --NHheteroaryl, --NHheterocycle, or
--S(O).sub.2NR.sub.cR.sub.d;
[0652] each Z.sup.14 is independently selected from --NO.sub.2,
.dbd.NOR.sub.a, --CN, --(C.sub.y C.sub.7)halocarbocycle,
--O(C.sub.3-C.sub.7)halocarbocycle,
--S(C.sub.3-C.sub.7)halocarbocycle,
--S(O)(C.sub.3-C.sub.7)halocarbocycle,
--SO.sub.2(C.sub.3-C.sub.7)halocarbocycle,
--NR.sub.aSO.sub.2NR.sub.cR.sub.4,
--NR.sub.aSO.sub.2O(C.sub.3-C.sub.7)carbocycle,
--NR.sub.aSO.sub.2Oaryl, --OS(O).sub.2R.sub.a; wherein any
--(C.sub.3-C.sub.7)halocarbocycle of Z.sup.14 is optionally
substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, --OH,
--OR.sub.b, --CN, --NR.sub.aC(O).sub.2R.sub.b, -heteroaryl,
-heterocycle, --Oheteroaryl, --Oheterocycle, --NHheteroaryl,
--NHheterocycle, or --S(O).sub.2NR.sub.cR.sub.d;
[0653] each R.sub.a is independently H, (C.sub.1-C.sub.6)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)carbocycle, heterocycle, aryl,
aryl(C.sub.1-C.sub.6)alkyl-, heteroaryl or
heteroaryl(C.sub.1-C.sub.6)alkyl-; wherein any
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle, heterocycle,
aryl, or heteroaryl of R.sub.a is optionally substituted by
halogen, OH and cyano;
[0654] each R.sub.b is independently --(C.sub.1-C.sub.6)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)carbocycle, heterocycle, aryl,
aryl(C.sub.1-C.sub.6)alkyl-, heteroaryl or heteroaryl(C.sub.r
C.sub.6)alkyl-; wherein any (C.sub.1-C.sub.6)alkyl,
--(C.sub.2-C.sub.6)alkenyl, --(C.sub.2-C.sub.6)alkynyl,
(C.sub.3-C.sub.7)carbocycle, heterocycle, aryl, or heteroaryl of
R.sub.b is optionally substituted by halogen, OH and cyano;
[0655] R.sub.c and R.sub.d are each independently selected from H,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle, aryl,
aryl(C.sub.1-C.sub.6)alkyl-, heterocycle, heteroaryl or
heteroaryl(C.sub.1-C.sub.6)allyl- wherein any
(C.sub.1-C.sub.6)alkyl, --(C.sub.2-C.sub.6)alkenyl,
--(C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.7)carbocycle,
heterocycle, aryl, or heteroaryl of R.sub.e or R.sub.d is
optionally substituted by halogen, OH and cyano; or R.sub.c and
R.sub.d together with the nitrogen to which they are attached form
a heterocycle; wherein any heterocycle of R.sub.c and R.sub.d
together with the nitrogen to which they are attached is optionally
substituted by halogen, OH or cyano;
[0656] each R.sub.e is independently selected from --OR.sub.a,
(C.sub.1-C.sub.6)alkyl or (C.sub.3-C.sub.7)carbocycle wherein
(C.sub.1-C.sub.6)alkyl or (C.sub.3-C.sub.7)carbocycle is
substituted by one or more Z.sub.d and optionally substituted with
one or more Z.sub.1; --(C.sub.2-C.sub.6)haloalkyl,
--(C.sub.2-C.sub.6)alkenyl, or --(C.sub.2-C.sub.6)alkynyl wherein
any haloalkyl, alkenyl or alkynyl is optionally substituted with
one or more Z.sub.1; aryl, heterocycle or heteroaryl wherein aryl,
heterocycle or heteroaryl is substituted by one or more
Z.sub.c;
[0657] each R.sub.f is independently selected from --R.sub.g,
--OR.sub.a, --(C.sub.1-C.sub.6)alkyl-Z.sup.6, --SO.sub.2R.sub.g,
--C(O)R.sub.g, C(O)OR.sub.g, or --C(O)NR.sub.eR.sub.g; and
[0658] each R.sub.g is independently selected from --OR.sub.a,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)carbocycle
(C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle or heteroaryl wherein
any (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)carbocycle
--(C.sub.1-C.sub.6)haloalkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, aryl, heterocycle or heteroaryl of
R.sub.g is optionally substituted with one or more Z.sub.1
groups;
[0659] or a salt thereof.
[0660] In one embodiment, the compounds of formula I include:
##STR00063## ##STR00064##
[0661] and salts thereof.
[0662] In another embodiment, the compounds of formula I
include:
##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069##
##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074##
##STR00075## ##STR00076##
[0663] and salts thereof.
[0664] In one embodiment, the compounds of formula I include:
##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081##
##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086##
##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091##
##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096##
##STR00097## ##STR00098## ##STR00099## ##STR00100##
and salts thereof.
[0665] In one embodiment, the compounds of formula I include:
##STR00101## ##STR00102##
and salts thereof.
General Synthetic Procedures
[0666] Schemes 1, 2 and 3 are provided as further embodiments of
the invention and illustrate general methods which were used to
prepare compounds of formula I and which can be used to prepare
additional compounds of formula I. Schemes 4-11 outline methods
that were used or can be used to prepare compounds of formula
I.
##STR00103## ##STR00104##
[0667] Cyclocondensation of a substituted hydroxyaniline with a
substituted, unsaturated aldehyde leads to quinolinols. Bromination
can be achieved using electrophilic sources of bromine such as NBS.
The phenol can be activated by transforming to a leaving group such
as trifluoromethanesulfonate by treatment with
trifluoromethanesulfonic anhydride and an appropriate base such as
2,6-lutidine. Regioselective palladium catalysed cross-coupling
reactions (e.g. Suzuki or Stille) can be used to alkylate the
quinoline with a vinyl group which can then be asymmetrically
di-hydroxylated using reagent mixtures such as AD-mix-.alpha..
Selective protection of the primary hydroxyl can be achieved with
bulky protecting groups, such as pivaloyl chloride. Formation of
the R.sup.3 group can be achieved by alkylation of the secondary
alcohol by various methods. Palladium catalysed cross coupling
reactions (e.g. Suzuki or Stille) can be used to install the
R.sup.4 group. Following hydrolysis of the protecting group, the
primary alcohol may then be oxidized to produce desired
compounds.
##STR00105## ##STR00106##
[0668] Alternatively, cyclocondensation of a halogenated aniline
starting material that is substituted at R.sup.4 can undergo
cyclocondensation with a substituted, unsaturated aldehyde can
deliver R.sup.4 substituted, R.sup.3 halogenated quinolines
directly. These can be further elaborated similarly to the methods
described for Scheme 1 to produce desired compounds.
##STR00107##
[0669] Generation of a quinolinone intermediate is achieved by
N-oxidation of the quinoline with a reagent such as mCPBA, followed
by acylation, thermal rearrangement, and selective removal of the
acetate. Deprotonation of the quinolinone followed by methods to
favor O-alkylation when treated with an appropriate electrophile
allow for substituents at R.sup.7 to be produced wherein the
R.sup.7 group is an ether. Subsequent hydrolysis and oxidation can
provide compounds of formula I with R.sup.7 ether groups.
##STR00108##
[0670] Deprotonation of the quinolinone followed by methods to
favor N-alkylation when treated with an appropriate electrophile
can yield desired alkylated quinolinone analogues with R.sup.13
modifications. Subsequent hydrolysis and oxidation produces desired
compounds.
##STR00109##
[0671] The quinolinyl triflate can be made from the quinolinone.
Cross coupling reactions with the triflate (e.g. Suzuki and
Sonagashira reaction) can introduce different R.sup.7 moieties.
Hydrolysis and oxidation can yield the desired compounds.
##STR00110##
[0672] The quinolinone can be converted to 2-chloroquinoline by
treatment with reagents such as phosphorous oxychloride.
Nucleophilic aromatic substitution can introduce different R.sup.7
groups wherein the R.sup.7 is linked through a heteroatom.
Hydrolysis and oxidation can produce the desired analogs.
##STR00111##
[0673] Deprotonation of 2-chloroquinoline, followed by reaction
with trimethyl borate can generate the boronic acid. Zinc and
acetic acid can be used to reduce the substituted chloroquinoline
to the quinoline. Cross coupling and subsequent hydrolysis and
oxidation can provide analogs with different R.sup.6 moieties.
##STR00112##
[0674] The methylquinoline can be oxidized with mCPBA to give the
N-oxide, which can react with acetic anhydride and rearrange to
yield the hydroxymethylquinoline. Oxidation of the alcohol can
provide the carboxylic acid. Coupling with different amines can
provide R.sup.7 amide moieties. Subsequent hydrolysis can generate
compounds of formula I with R.sup.7 amides.
##STR00113##
[0675] The quinoline carboxylic acid can be converted to a primary
amine via a Curtius rearrangement which can be converted to
additional R.sup.7 groups wherein the R.sup.7 group is an amine.
Subsequent hydrolysis can provide compounds of formula I with
R.sup.7 amine groups.
##STR00114##
[0676] The hydroxymethylquinoline can be converted to mesylate,
which can be reacted with different nucleophiles to provide R.sup.7
groups wherein the R.sup.7 group is represented by the general
formula "--CH.sub.2XR" wherein X is O, S or NR'. Subsequent
hydrolysis can generate compounds of formula I.
##STR00115##
[0677] The quinolinyl triflate can react with Grignard or
alkyl-lithium reagents in the presence of a catalyst such as
Fe(AcAc).sub.3 to give the corresponding quinoline. Subsequent
deprotection and oxidation can generate compounds of formula I.
Prodrugs
[0678] In one embodiment, the invention provides for a prodrug of a
compound of the invention. The term "prodrug" as used herein refers
to any compound that when administered to a biological system
generates a compound of the invention that inhibits the replication
of HIV ("the active inhibitory compound"). The compound may be
formed from the prodrug as a result of: (i) spontaneous chemical
reaction(s), (ii) enzyme catalyzed chemical reaction(s), (iii)
photolysis, and/or (iv) metabolic chemical reaction(s).
[0679] "Prodrug moiety" refers to a labile functional group which
separates from the active inhibitory compound during metabolism,
systemically, inside a cell, by hydrolysis, enzymatic cleavage, or
by some other process (Bundgaard, Hans, "Design and Application of
Prodrugs" in A Textbook of Drug Design and Development (1991), P.
Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic
Publishers, pp. 113-191). Enzymes which are capable of an enzymatic
activation mechanism with the prodrug compounds of the invention
include, but are not limited to, amidases, esterases, microbial
enzymes, phospholipases, cholinesterases, and phosphases. Prodrug
moieties can serve to enhance solubility, absorption and
lipophilicity to optimize drug delivery, bioavailability and
efficacy. A prodrug moiety may include an active metabolite or drug
itself.
[0680] Exemplary prodrug moieties include the hydrolytically
sensitive or labile acyloxymethyl esters CH.sub.2OC(.dbd.O)R.sup.99
and acyloxymethyl carbonates CH.sub.2C(.dbd.O)OR.sup.99 where
R.sup.99 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted
alkyl, C.sub.6-C.sub.20 aryl or C.sub.6-C.sub.20 substituted aryl.
The acyloxyalkyl ester was first used as a prodrug strategy for
carboxylic acids and then applied to phosphates and phosphonates by
Farquhar et al. (1983) J. Pharm. Sci. 72: 324; also U.S. Pat. Nos.
4,816,570, 4,968,788, 5663159 and 5792756. Subsequently, the
acyloxyalkyl ester was used to deliver phosphonic acids across cell
membranes and to enhance oral bioavailability. A close variant of
the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester
(carbonate), may also enhance oral bioavailability as a prodrug
moiety in the compounds of the combinations of the invention. An
exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM)
CH.sub.2C(.dbd.O)C(CH.sub.3).sub.3. An exemplary acyloxymethyl
carbonate prodrug moiety is pivaloyloxymethylcarbonate
(POC)--CH.sub.2OC(.dbd.O)OC(CH.sub.3).sub.3.
[0681] Aryl esters of phosphorus groups, especially phenyl esters,
are reported to enhance oral bioavailability (De Lombaert et al.
(1994) J. Med. Chem. 37: 498). Phenyl esters containing a
carboxylic ester ortho to a phosphate have also been described
(Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl
esters are reported to generate parent phosphonic acids. In some
cases, substituents at the ortho- or para-position may accelerate
the hydrolysis. Benzyl analogs with an acylated phenol or an
alkylated phenol may generate the phenolic compound through the
action of enzymes, e.g., esterases, oxidases, etc., which in turn
undergoes cleavage at the benzylic C--O bond to generate phosphoric
acid and a quinone methide intermediate. Examples of this class of
prodrugs are described by Mitchell et al. (1992) J. Chem. Soc.
Perkin Trans. II 2345; Glazier WO 91/19721. Still other benzylic
prodrugs have been described containing a carboxylic
ester-containing group attached to the benzylic methylene (Glazier
WO 91/19721). Thio-containing prodrugs are reported to be useful
for the intracellular delivery of phosphonate drugs. These
proesters contain an ethylthio group in which the thiol group is
either esterified with an acyl group or combined with another thiol
group to form a disulfide. De-esterification or reduction of the
disulfide generates the free thio intermediate which subsequently
breaks down to the phosphoric acid and episulfide (Puech et al.
(1993) Antiviral Res., 22: 155-174; Benzaria et al. (1996) J. Med.
Chem. 39: 4958).
Pharmaceutical Formulations
[0682] The compounds of this invention are formulated with
conventional carriers and excipients, which will be selected in
accord with ordinary practice. Tablets will contain excipients,
glidants, fillers, binders and the like. Aqueous formulations are
prepared in sterile form, and when intended for delivery by other
than oral administration generally will be isotonic. All
formulations will optionally contain excipients such as those set
forth in the Handbook of Pharmaceutical Excipients (1986).
Excipients include ascorbic acid and other antioxidants, chelating
agents such as EDTA, carbohydrates such as dextrin,
hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid
and the like. The pH of the formulations ranges from about 3 to
about 11, but is ordinarily about 7 to 10.
[0683] While it is possible for the active ingredients to be
administered alone it may be preferable to present them as
pharmaceutical formulations. The formulations, both for veterinary
and for human use, of the invention comprise at least one active
ingredient, as above defined, together with one or more acceptable
carriers and optionally other therapeutic ingredients. The
carrier(s) must be "acceptable" in the sense of being compatible
with the other ingredients of the formulation and physiologically
innocuous to the recipient thereof.
[0684] The formulations include those suitable for the foregoing
administration routes.
[0685] The formulations may conveniently be presented in unit
dosage form and may be prepared by any of the methods well known in
the art of pharmacy. Techniques and formulations generally are
found in Remington's Pharmaceutical Sciences (Mack Publishing Co.,
Easton, Pa.). Such methods include the step of bringing into
association the active ingredient with the carrier which
constitutes one or more accessory ingredients. In general the
formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the
product.
[0686] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets or tablets each containing a predetermined amount of the
active ingredient; as a powder or granules; as a solution or a
suspension in an aqueous or non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be administered as a bolus, electuary or
paste.
[0687] A tablet is made by compression or molding, optionally with
one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, preservative,
surface active or dispersing agent. Molded tablets may be made by
molding in a suitable machine a mixture of the powdered active
ingredient moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and optionally are formulated so as
to provide slow or controlled release of the active ingredient
therefrom.
[0688] For administration to the eye or other external tissues
e.g., mouth and skin, the formulations are preferably applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of, for example, 0.075 to 20% w/w (including active
ingredient(s) in a range between 0.1% and 20% in increments of 0.1%
w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w
and most preferably 0.5 to 10% w/w. When formulated in an ointment,
the active ingredients may be employed with either a paraffinic or
a water-miscible ointment base. Alternatively, the active
ingredients may be formulated in a cream with an oil-in-water cream
base.
[0689] If desired, the aqueous phase of the cream base may include,
for example, at least 30% w/w of a polyhydric alcohol, i.e. an
alcohol having two or more hydroxyl groups such as propylene
glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and
polyethylene glycol (including PEG 400) and mixtures thereof. The
topical formulations may desirably include a compound which
enhances absorption or penetration of the active ingredient through
the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethyl sulfoxide and related
analogs.
[0690] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier (otherwise known as an
emulgent), it desirably comprises a mixture of at least one
emulsifier with a fat or an oil or with both a fat and an oil.
Preferably, a hydrophilic emulsifier is included together with a
lipophilic emulsifier which acts as a stabilizer. It is also
preferred to include both an oil and a fat. Together, the
emulsifier(s) with or without stabilizer(s) make up the so-called
emulsifying wax, and the wax together with the oil and fat make up
the so-called emulsifying ointment base which forms the oily
dispersed phase of the cream formulations.
[0691] Emulgents and emulsion stabilizers suitable for use in the
formulation of the invention include Tween.RTM. 60, Span.RTM. 80,
cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl
mono-stearate and sodium lauryl sulfate.
[0692] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties. The cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters known as Crodamol CAP may be
used, the last three being preferred esters. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils are used.
[0693] Pharmaceutical formulations according to the present
invention comprise one or more compounds of the invention together
with one or more pharmaceutically acceptable carriers or excipients
and optionally other therapeutic agents. Pharmaceutical
formulations containing the active ingredient may be in any form
suitable for the intended method of administration. When used for
oral use for example, tablets, troches, lozenges, aqueous or oil
suspensions, dispersible powders or granules, emulsions, hard or
soft capsules, syrups or elixirs may be prepared. Compositions
intended for oral use may be prepared according to any method known
to the art for the manufacture of pharmaceutical compositions and
such compositions may contain one or more agents including
sweetening agents, flavoring agents, coloring agents and preserving
agents, in order to provide a palatable preparation. Tablets
containing the active ingredient in admixture with non-toxic
pharmaceutically acceptable excipient which are suitable for
manufacture of tablets are acceptable. These excipients may be, for
example, inert diluents, such as calcium or sodium carbonate,
lactose, lactose monohydrate, croscarmellose sodium, povidone,
calcium or sodium phosphate; granulating and disintegrating agents,
such as maize starch, or alginic acid; binding agents, such as
cellulose, microcrystalline cellulose, starch, gelatin or acacia;
and lubricating agents, such as magnesium stearate, stearic acid or
talc. Tablets may be uncoated or may be coated by known techniques
including microencapsulation to delay disintegration and adsorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate alone or with
a wax may be employed.
[0694] Formulations for oral use may be also presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example calcium phosphate or kaolin, or as soft
gelatin capsules wherein the active ingredient is mixed with water
or an oil medium, such as peanut oil, liquid paraffin or olive
oil.
[0695] Aqueous suspensions of the invention contain the active
materials in admixture with excipients suitable for the manufacture
of aqueous suspensions. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropyl methylcelluose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension may also contain one or more preservatives such as ethyl
or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose or saccharin.
[0696] Oil suspensions may be formulated by suspending the active
ingredient in a vegetable oil, such as arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oral suspensions may contain a thickening agent, such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such
as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an antioxidant such as ascorbic
acid.
[0697] Dispersible powders and granules of the invention suitable
for preparation of an aqueous suspension by the addition of water
provide the active ingredient in admixture with a dispersing or
wetting agent, a suspending agent, and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are
exemplified by those disclosed above. Additional excipients, for
example sweetening, flavoring and coloring agents, may also be
present.
[0698] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, such as olive oil or arachis oil, a mineral oil,
such as liquid paraffin, or a mixture of these. Suitable
emulsifying agents include naturally-occurring gums, such as gum
acacia and gum tragacanth, naturally occurring phosphatides, such
as soybean lecithin, esters or partial esters derived from fatty
acids and hexitol anhydrides, such as sorbitan monooleate, and
condensation products of these partial esters with ethylene oxide,
such as polyoxyethylene sorbitan monooleate. The emulsion may also
contain sweetening and flavoring agents. Syrups and elixirs may be
formulated with sweetening agents, such as glycerol, sorbitol or
sucrose. Such formulations may also contain a demulcent, a
preservative, a flavoring or a coloring agent.
[0699] The pharmaceutical compositions of the invention may be in
the form of a sterile injectable preparation, such as a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, such as a solution in
1,3-butane-diol or prepared as a lyophilized powder. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile fixed oils may conventionally be employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid may likewise be used in
the preparation of injectables.
[0700] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion may contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur.
[0701] Formulations suitable for administration to the eye include
eye drops wherein the active ingredient is dissolved or suspended
in a suitable carrier, especially an aqueous solvent for the active
ingredient. The active ingredient is preferably present in such
formulations in a concentration of 0.5 to 20%, advantageously 0.5
to 10% particularly about 1.5% w/w.
[0702] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0703] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0704] Formulations suitable for intrapulmonary or nasal
administration have a particle size for example in the range of 0.1
to 500 microns (including particle sizes in a range between 0.1 and
500 microns in increments microns such as 0.5, 1, 30 microns, 35
microns, etc.), which is administered by rapid inhalation through
the nasal passage or by inhalation through the mouth so as to reach
the alveolar sacs. Suitable formulations include aqueous or oily
solutions of the active ingredient. Formulations suitable for
aerosol or dry powder administration may be prepared according to
conventional methods and may be delivered with other therapeutic
agents.
[0705] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0706] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents.
[0707] The formulations are presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water for
injection, immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
[0708] It should be understood that in addition to the ingredients
particularly mentioned above the formulations of this invention may
include other agents conventional in the art having regard to the
type of formulation in question, for example those suitable for
oral administration may include flavoring agents.
[0709] The invention further provides veterinary compositions
comprising at least one active ingredient as above defined together
with a veterinary carrier.
[0710] Veterinary carriers are materials useful for the purpose of
administering the composition and may be solid, liquid or gaseous
materials which are otherwise inert or acceptable in the veterinary
art and are compatible with the active ingredient. These veterinary
compositions may be administered orally, parenterally or by any
other desired route.
[0711] Compounds of the invention can also be formulated to provide
controlled release of the active ingredient to allow less frequent
dosing or to improve the pharmacokinetic or toxicity profile of the
active ingredient. Accordingly, the invention also provides
compositions comprising one or more compounds of the invention
formulated for sustained or controlled release.
[0712] Effective dose of active ingredient depends at least on the
nature of the condition being treated, toxicity, whether the
compound is being used prophylactically (lower doses), the method
of delivery, and the pharmaceutical formulation, and will be
determined by the clinician using conventional dose escalation
studies.
Routes of Administration
[0713] One or more compounds of the invention (herein referred to
as the active ingredients) are administered by any route
appropriate to the condition to be treated. Suitable routes include
oral, rectal, nasal, topical (including buccal and sublingual),
vaginal and parenteral (including subcutaneous, intramuscular,
intravenous, intradermal, intrathecal and epidural), and the like.
It will be appreciated that the preferred route may vary with for
example the condition of the recipient. An advantage of the
compounds of this invention is that they are orally bioavailable
and can be dosed orally.
[0714] The antiviral properties of a compound of the invention may
be determined using Test A described below.
Test A: Antiviral Assays in MT4 Cells
[0715] For the antiviral assay utilizing MT-4 cells, 0.4 .mu.L of
189X test concentration of 3-fold serially diluted compound in DMSO
was added to 40 .mu.L of cell growth medium (RPMI 1640, 10% FBS, 1%
penicillin/Streptomycin, 1% L-Glutamine, 1% HEPES) in each well of
384-well assay plates (10 concentrations) in quadruplicate.
[0716] 1 mL aliquots of 2.times.10e6 MT-4 cells are pre-infected
for 1 and 3 hrs respectively, @ 37.degree. C. with 25 .mu.L (MT4)
or of either cell growth medium (mock-infected) or a fresh 1:250
dilution of an HIV-IIIb concentrated ABI stock (0.004 m.o.i. for
MT4 cells). Infected and uninfected cells are diluted in cell
growth medium and 35 uL of 2000 (for MT4) cells is added to each
well of the assay plates.
[0717] Assay plates were then incubated in a 37.degree. C.
incubator. After 5 days of incubation, 25 .mu.l of 2.times.
concentrated CellTiter-Glo.TM. Reagent (catalog #G7573, Promega
Biosciences, Inc., Madison, Wis.) was added to each well of the
assay plate. Cell lysis was carried out by incubating at room
temperature for 2-3 min and then chemiluminescence was read using
the Envision reader (PerkinElmer).
[0718] Compounds of the present invention demonstrate antiviral
activity in this assay (Test A) as depicted in the table below.
TABLE-US-00001 Compound Number EC50 (nM) 1L 170 2K 55 3L 1059 4J
543 5J 19 6D 20 7J 160 8L 559 9 173 10 897 11 479 12 210 13 150 14
983 15 334 16 220 17 359 19 53000 20 1744 21 231 22 1075 23 26185
24 29783 25 346 26 45 27 23 28 43 29 939 30 153 31 105 32 108 33 95
34 266 35 157 36 20 37A 36 37B 46 38 68 39 11 40 51 41 26 42 46 43
27 44 18 45 29150 46 20 47 14 48 26 49 27 50 24 51 30 52 25 53 360
54 87 55 41 56 40 57 20 58 14 59 321 60 305 61 119 62 72 63 183 64
290 65A 85 65B 55 66 297 67 273 68 29150 69 82 70 206 71 118 72 194
73 247 74 92 75 38 76 267 77 135 78 163 79 86 80 52 81 69 82 171 83
42 84 330 85 131 86 78 87 175 88 514 89 42 90 67 91 73 92 300 93 94
94 149 95 54 96 37 97 898 98 251 99 12 100 75 101 367 102A 13 102B
110 103 25 104 720 105 105 106 25 107 n.d. 108 n.d. 109 n.d 110
n.d. 111 352 112 n.d. n.d. (not determined)
[0719] In certain embodiments, the compounds demonstrate an EC50 of
<50 .mu.M. In certain embodiments, the compounds demonstrate an
EC50 of <30 .mu.M. In certain embodiments, the compounds
demonstrate an EC50 of <10 .mu.M. In certain embodiments, the
compounds demonstrate an EC50 of <1 .mu.M.
[0720] The specific pharmacological responses observed may vary
according to and depending on the particular active compound
selected or whether there are present pharmaceutical carriers, as
well as the type of formulation and mode of administration
employed, and such expected variations or differences in the
results are contemplated in accordance with practice of the present
invention.
[0721] The invention has been described with reference to various
specific and preferred embodiments and techniques. However, it
should be understood that many variations and modifications may be
made while remaining within the spirit and scope of the
invention.
[0722] The invention will now be illustrated by the following
non-limiting Examples.
Example 1
Preparation of
(S)-2-tert-butoxy-2-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)ac-
etic acid (1L)
##STR00116## ##STR00117##
[0724] A stock solution of periodic acid/chromium trioxide was
prepared according to WO 99/52850 by dissolving periodic acid (11.4
g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet
acetonitrile (0.75% H.sub.2O) to a volume of 114 mL. This stock
solution (0.80 mL) was added to a solution of
(S)-2-tert-butoxy-2-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)et-
hanol (1K) (11 mg, 0.027 mmol) in wet acetonitrile (3.0 mL), 0.75%
H.sub.2O) at 0.degree. C. The reaction mixture was stirred for 30
minutes at 0.degree. C. and quenched with 1.5 M K.sub.2HPO.sub.4
solution. Ethyl acetate was added and the organic layer separated
and washed with 1:1 brine/H.sub.2O (2.times.) and saturated
NaHSO.sub.3/brine. The organic layer was dried (MgSO.sub.4) and
concentrated and purified by prep-HPLC to give 1L as a TFA salt (8
mg, 57%). .sup.1H-NMR 300 MHz, (CD.sub.3OD) .delta. 8.19 (s, 1H),
8.17 (d, 1H), 7.70-7.52 (m, 4H), 7.40-7.30 (m, 1H), 2.89 (s, 3H),
1.01 (s, 9H); LCMS-ESI.sup.+ (m/z): [M-FH].sup.+ calcd for
C.sub.22H.sub.22Cl.sub.2NO.sub.3: 419.3. Found: 418.1, 420.1,
422.1.
Preparation of
(S)-2-tert-butoxy-2-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)et-
hanol (1K)
Step 1.
[0725] Preparation of 7-chloro-6-methoxy-2-methylquinoline (1B): To
3-chloro-4-methoxyaniline (1A) (5.0 g, 31.7 mmol) was added 6 M HCl
(100 mL) and the reaction was heated to 100.degree. C. with
stirring. Toluene (30 mL) was added followed by the slow addition
of crotonaldehyde (5.3 mL, 63.5 mmol) at 100.degree. C. The mixture
was stirred at 100.degree. C. for 2 hours and cooled to room
temperature. The water layer was separated and neutralized with 2 M
NaOH solution to pH 8. The solid that formed was filtered and
collected. The crude product was purified by flash column
chromatography to give 1B as white solid (3.3 g, 50%).
LCMS-ESI.sup.+ (m/z): 208.2, 210.2 (M+H).sup.+.
Step 2.
[0726] Preparation of 7-chloro-2-methylquinolin-6-ol (1C): To a
stirred solution of 7-chloro-6-methoxy-2-methylquinoline (1B) (1.22
g, 5.9 mmol) in dichloromethane (15 mL) was added BBr.sub.3 (23.6
mL 1 M DCM solution, 23.6 mmol) at 0.degree. C. The mixture was
stirred at 0.degree. C. for 2 hours and quenched by the slow
addition of a NaHCO.sub.3 solution. The mixture was extracted with
ethyl acetate. The organic layer was washed with brine, dried and
concentrated. The residue was purified by column chromatography to
give the pure product 1C (0.91 g, 80%). LCMS-ESI.sup.+ (m/z):
194.1, 196.1 (M+H).sup.+.
Step 3.
[0727] Preparation of 5-bromo-7-chloro-2-methylquinolin-6-ol (1D):
To a stirred solution of 7-chloro-2-methylquinolin-6-ol (1C) (450
mg, 2.3 mmol) in acetic acid (15 mL) was added Br.sub.2 (0.13 mL,
2.4 mmol) at ambient temperature. The mixture was stirred at
ambient temperature for 2 hours. The solid that formed was filtered
and collected to give 1D as an off-white solid as the HBr salt (847
mg, 100%). LCMS-ESI.sup.+ (m/z): 281.1, 283.1 (M+H).sup.+.
Step 4.
[0728] Preparation of
7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-ol (1E):
Pd(PPh.sub.3).sub.4 (120 mg, 0.1 mmol) was added to a mixture of
5-bromo-7-chloro-2-methylquinolin-6-ol (1D) (345 mg, 1.04 mmol),
4-chlorophenylboronic acid (326 mg, 2.09 mmol) and K.sub.2CO.sub.3
(2.3 mL 2 M in water, 4.7 mmol) in 1,2-dimethoxyethane (10 mL). The
reaction mixture was flushed with nitrogen, heated at 80.degree. C.
for 16 hours, and then the volatile component was removed in vacuo.
The residue was dissolved in ethyl acetate (100 mL), washed with a
NaHCO.sub.3 solution, water and brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The obtained residue was
purified by flash chromatography to provide 1E as a white solid
(147 mg, 47%). LCMS-ESI.sup.+ (m/z): 304.2, 306.2 (M+H).sup.+.
Step 5.
[0729] Preparation of
7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl
trifluoromethanesulfonate (1F): To a stirred solution of
7-chloro-5-(4-chloro-phenyl)-2-methylquinolin-6-ol (1E) (138 mg,
0.46 mmol) in dichloromethane (4 mL) and pyridine (1.5 mL) was
added Tf.sub.2O (0.16 mL, 0.92 mmol) at 0.degree. C. The mixture
was stirred at room temperature for 2 hours and quenched by the
slow addition of a NaHCO.sub.3 solution. The mixture was extracted
with ethyl acetate. The organic layer was washed with brine, dried
and concentrated to get a brown solid (194 mg, 97%). LCMS-ESI.sup.+
(m/z): 436.0, 437.9 (M+H).sup.+. The crude product 1F was used on
next step reaction without further purification.
Step 6.
[0730] Preparation of
7-chloro-5-(4-chlorophenyl)-2-methyl-6-vinylquinoline (1G):
Pd(PPh.sub.3).sub.4 (52 mg, 0.045 mmol) and
PdCl.sub.2(PPh.sub.3).sub.2 (32 mg, 0.045 mmol) were added to a
mixture 7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl
trifluoromethanesulfonate (1F) (194 mg, 0.45 mmol),
tributyl(vinyl)stannane (0.17 mL, 0.58 mmol), lithium chloride (57
mg, 1.4 mmol) and 2,6-di-tert-butyl-4-methylphenol (cat. amount) in
1,4-dioxane (8 mL). The reaction mixture was flushed with nitrogen,
heated at 80.degree. C. for 16 hours, and then the volatile
component was removed in vacuo. The residue was dissolved in ethyl
acetate (100 mL), washed with a NaHCO.sub.3 solution, water and
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The obtained residue was purified by flash chromatography to
provide the desired product 1G (50 mg, 35%). LCMS-ESI.sup.+ (m/z):
314.2, 316.2 (M+H).sup.+.
Step 7.
[0731] Preparation of
(S)-1-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)ethane-1,2-diol
(1H): AD-mix-.alpha. (1 g, excess) was added to a mixed solvent of
t-butanol and water (4 mL/4 mL) and stirred at room temperature for
5 min and cooled to 0.degree. C. The mixture was transferred to
another flask containing
7-chloro-5-(4-chlorophenyl)-2-methyl-6-vinylquinoline (1G) (30 mg,
0.096 mmol) and stirred at 0.degree. C. for 16 hours. The mixture
was diluted with ethyl acetate, washed with NaHCO.sub.3 solution,
water and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The obtained residue was purified by flash
chromatography to provide the desired product 1H (28 mg, 84%).
LCMS-ESI.sup.+ (m/z): 348.2, 350.2 (M+H).sup.+.
Step 8.
[0732] Preparation of
(S)-2-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)-2-hydroxyethyl
pivalate (11): To a stirred solution of
(S)-1-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-ypethane-1,2-diol
(1H) (28 mg, 0.081 mmol) in dichloromethane (2 mL) and pyridine
(0.5 mL) was added trimethyl acetylchloride (0.020 mL, 0.16 mmol)
at 0.degree. C. The mixture was stirred at room temperature for 2
hours and quenched by the slow addition of a NaHCO.sub.3 solution.
The mixture was extracted with ethyl acetate. The organic layer was
washed with brine, dried and concentrated in vacuo. The obtained
residue was purified by flash chromatography to provide the desired
product 1I (25 mg, 72%). LCMS-ESI.sup.+ (m/z): 432.2, 434.2
(M+H).sup.+.
Step 9.
[0733] Preparation of
(S)-2-tert-butoxy-2-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)et-
hyl pivalate (1J): To a stirred solution of
(S)-2-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)-2-hydroxyethyl
pivalate (H) (25 mg, 0.058 mmol) in t-butylacetate (3 mL) was added
70% perchloric acid (0.02 mL, 0.23 mmol) at 0.degree. C. The
mixture was stirred at room temperature for 2 hours and quenched by
the slow addition of a NaHCO.sub.3 solution. The mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried and concentrated in vacuo. The obtained residue was
purified by flash chromatography to provide the desired product 1J
(22 mg, 78%). LCMS-ESI.sup.+ (m/z): 488.2, 490.2 (M+H).sup.+.
Step 10.
[0734] Preparation of
(S)-2-tert-butoxy-2-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)et-
hanol (1K): To a stirred solution of
(S)-2-tert-butoxy-2-(7-chloro-5-(4-chlorophenyl)-2-methylquinolin-6-yl)et-
hyl pivalate (1J) (22 mg, 0.045 mmol) in THF and methanol (3 mL/1
mL) was added 1 M NaOH solution (1 mL, excess) at 0.degree. C. The
mixture was stirred at room temperature for 16 hours and diluted
with water. The mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried and concentrated in
vacuo. The obtained residue was purified by flash chromatography to
provide the desired product 1K (11 mg, 61%). LCMS-ESI.sup.+ (m/z):
404.2, 406.2 (M+H).sup.+.
Example 2
Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)acetic
acid (2K)
##STR00118## ##STR00119##
[0736]
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)a-
cetic acid (2K) was prepared following the procedure used to
prepare compound 1L of Example 1, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethanol
(2J) was used instead of compound 1K. .sup.1H-NMR 300 MHz,
(CD.sub.3OD) .delta. 8.31 (d, 1H), 7.97 (s, 1H), 7.73 (d, 1H),
7.70-7.60 (m, 3H), 7.42-7.38 (m, 1H), 5.25 (s, 1H), 2.96 (s, 3H),
2.78 (s, 3H), 0.98 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd
for C.sub.23H.sub.25ClNO.sub.3: 398.9. Found: 398.2, 400.1.
[0737] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethanol
(2J)
Step 1.
[0738] Preparation of 2,7-dimethylquinolin-6-ol (2B): Compound 2B
was prepared following the procedure used to prepare compound 1B of
Example 1, except that 4-amino-2-methylphenol (2A) was used instead
of compound 1A. LCMS-ESI.sup.+ (m/z): 174.2 (M+H).sup.+.
Step 2.
[0739] Preparation of 5-bromo-2,7-dimethylquinolin-6-ol (2C):
Compound 2C was prepared following the procedure used to prepare
compound 1D of Example 1, except that 2,7-dimethylquinolin-6-ol
(2B) was used instead of compound 1C. LCMS-ESI.sup.+ (m/z): 252.2,
254.2 (M+H).sup.+.
Step 3.
[0740] Preparation of 5-(4-chlorophenyl)-2,7-dimethylquinolin-6-ol
(2D): Compound 2D was prepared following the procedure used to
prepare compound 1E of Example 1, except that
5-bromo-2,7-dimethylquinolin-6-ol (2C) was used instead of compound
1D.
[0741] LCMS-ESI.sup.+ (m/z): 284.2, 286.2 (M+H).sup.+.
Step 4.
[0742] Preparation of 5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl
trifluoromethanesulfonate (2E): Compound 2E was prepared following
the procedure used to prepare compound 1F of Example 1, except that
5-(4-chlorophenyl)-2,7-dimethylquinolin-6-ol (2D) was used instead
of compound 1E. LCMS-ESI.sup.+ (m/z): 416.0, 418.0 (M+H).sup.+.
Step 5.
[0743] Preparation of
5-(4-chlorophenyl)-2,7-dimethyl-6-vinylquinoline (2F): Compound 2F
was prepared following the procedure used to prepare compound 1G of
Example 1, except that 5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl
trifluoromethanesulfonate (2E) was used instead of compound 1F.
LCMS-ESI.sup.+ (m/z): 294.3, 296.3 (M+H).sup.+.
Step 6.
[0744] Preparation of
(S)-1-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethane-1,2-diol
(2G): Compound 2G was prepared following the procedure used to
prepare compound 1H of Example 1, except that
5-(4-chlorophenyl)-2,7-dimethyl-6-vinylquinoline (2F) was used
instead of compound 1G. LCMS-ESI.sup.+ (m/z): 328.2, 330.2
(M+H).sup.+.
Step 7.
[0745] Preparation of
(S)-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)-2-hydroxyethyl
pivalate (211): Compound 2H was prepared following the procedure
used to prepare compound 1I of Example 1, except that
(S)-1-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-ypethane-1,2-diol
(2G) was used instead of compound 1H. LCMS-ESI.sup.+ (m/z): 412.3,
414.3 (M+H).sup.+.
Step 8.
[0746] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethyl
pivalate (21): Compound 21 was prepared following the procedure
used to prepare compound 1J of Example 1, except that
(S)-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)-2-hydroxyethyl
pivalate (211) was used instead of compound H.
[0747] LCMS-ESI.sup.+ (m/z): 468.3, 470.3 (M+H).sup.+.
Step 9.
[0748] Preparation
of(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethan-
ol (2J): Compound 2J was prepared following the procedure used to
prepare compound 1K of Example 1, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethyl
pivalate (21) was used instead of compound 1J. LCMS-ESI.sup.+
(m/z): 384.2, 386.2 (M+H).sup.+.
Example 3
Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)acetic
acid (3L)
##STR00120## ##STR00121##
[0750]
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)aceti-
c acid (3L) was prepared following the procedure used to prepare
compound 1L of Example 1, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)ethanol
(3K) was used instead of compound 1L. .sup.1H-NMR 300 MHz,
(CDCl.sub.3) 8.89-8.86 (m, 1H), 7.98 (s, 1H), 7.75-7.65 (m, 2H),
7.58-7.50 (m, 2H), 7.30-7.20 (m, 2H), 5.30 (s, 1H), 2.66 (s, 3H),
1.02 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.22H.sub.23ClNO.sub.3: 384.9. Found:384.1, 386.1.
Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)ethanol
(3K)
Step 1.
[0751] Preparation of 6-methoxy-7-methylquinoline (3B):
1-methoxy-2-methyl-4-nitrobenzene (3A) (5 g, 30.0 mmol),
3-amino-1-propanol (0.57 mL, 7.5 mmol), isopropanol (3.43 mL, 4.5
mmol), ruthenium(III) chloride hydrate (156 mg, 0.75 mmol),
triphenylphosphine (588 mg, 2.24 mmol), and tin(II) chloride
dihydrate (1.69 g, 7.5 mmol) in dioxane/H.sub.2O (67 mL/7 mL) were
placed in a stainless steel pressure vessel. After the system was
flushed with argon, the mixture was stirred at 180.degree. C. for
20 hours. The reaction mixture was filtered through a short silica
gel column (ethyl acetate/chloroform mixture) to eliminate
inorganic compounds and concentrated under reduced pressure. The
organic layer was poured into saturated brine, extracted with
chloroform, dried over anhydrous sodium sulfate, and evaporated
under reduced pressure. The residual oily material was separated by
column chromatography to give the product 3B (200 mg, 15%).
LCMS-ESI.sup.+ (m/z): 174.2 (M+H).sup.+.
Step 2.
[0752] Preparation of 7-methylquinolin-6-ol (3C): Compound 3C was
prepared following the procedure used to prepare compound 1C of
Example 1, except that 6-methoxy-7-methylquinoline (3B) was used
instead of compound 1B. LCMS-ESI.sup.+ (m/z): 160.2
(M+H).sup.+.
Step 3.
[0753] Preparation of 5-bromo-7-methylquinolin-6-ol (3D): Compound
3D was prepared following the procedure used to prepare compound 1D
of Example 1, except that 7-methylquinolin-6-ol (3C) was used
instead of compound 1C. LCMS-ESI.sup.+ (m/z): 238.1, 240.1
(M+H).sup.+.
Step 4.
[0754] Preparation of 5-(4-chlorophenyl)-7-methylquinolin-6-ol
(3E): Compound 3E was prepared following the procedure used to
prepare compound 1E of Example 1, except that
5-bromo-7-methylquinolin-6-ol (3D) was used instead of compound
1D.
[0755] LCMS-ESI.sup.+ (m/z): 270.2, 272.2 (M+H).sup.+.
Step 5.
[0756] Preparation of 5-(4-chlorophenyl)-7-methylquinolin-6-yl
trifluoromethanesulfonate (3F): Compound 3F was prepared following
the procedure used to prepare compound 1F of Example 1, except that
5-(4-chloro-phenyl)-7-methylquinolin-6-ol (3E) was used instead of
compound 1E. LCMS-ESI.sup.+ (m/z): 402.0, 404.0 (M+H).sup.+.
Step 6.
[0757] Preparation of 5-(4-chlorophenyl)-7-methyl-6-vinylquinoline
(3G): Compound 3G was prepared following the procedure used to
prepare compound 1G of Example 1, except that
5-(4-chlorophenyl)-7-methylquinolin-6-yl trifluoromethanesulfonate
(3F) was used instead of 1F. LCMS-ESI.sup.+ (m/z): 280.2, 282.2
(M+H).sup.+.
Step 7.
[0758] Preparation of
(S)-1-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)ethane-1,2-diol
(3H): Compound 3H was prepared following the procedure used to
prepare compound 1H of Example 1, except that
5-(4-chlorophenyl)-7-methyl-6-vinyl-quinoline (3G) was used instead
of compound 1G. LCMS-ESI.sup.+ (m/z): 314.2, 316.2 (M+H).sup.+.
Step 8.
[0759] Preparation of
(S)-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-hydroxyethyl
pivalate (31): Compound 31 was prepared following the procedure
used to prepare compound 1I of Example 1, except that
(S)-1-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)ethane-1,2-diol
(311) was used instead of compound 1H. LCMS-ESI.sup.+ (m/z): 398.2,
400.2 (M+H).sup.+.
Step 9.
[0760] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)ethyl
pivalate (3J): Compound 3J was prepared following the procedure
used to prepare compound 1J of Example 1, except that
(S)-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-hydroxyethyl
pivalate (31) was used instead of compound H.
[0761] LCMS-ESI.sup.+ (m/z): 454.3, 456.3 (M+H).sup.+.
Step 10.
[0762] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)ethanol
(3K): Compound 3K was prepared following the procedure used to
prepare compound 1K of example 1, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methylquinolin-6-yl)ethyl
pivalate (3J) was used instead of compound 1J. LCMS-ESI.sup.+
(m/z): 370.2, 372.2 (M+H).sup.+.
Example 4
Preparation of
(S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)acetic
acid (4J)
##STR00122## ##STR00123##
[0764]
(S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)aceti-
c acid (4J) was prepared following the procedure used to prepare
compound 1L of Example 1, except that
(S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)ethanol
(41) was used instead of compound 1K. .sup.1H-NMR 300 MHz,
(CD.sub.3OD) .delta. 8.97-8.91 (m, 1H), 8.86-8.82 (m, 1H), 8.11 (s,
1H), 7.95-7.90 (m, 1H), 7.72-7.65 (m, 3H), 7.50-7.45 (m, 1H), 5.23
(s, 1H), 2.73 (s, 3H), 0.99 (s, 9H); LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.22H.sub.23ClNO.sub.3: 384.9. Found:
384.1, 386.1.
Preparation of
(S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)ethanol
(4I)
Step 1.
[0765] Preparation of
8-(4-chlorophenyl)-7-methoxy-6-methylquinoline (4B): Compound 4B
was prepared following the procedure used to prepare compound 1E of
Example 1, except that 8-bromo-7-methoxy-6-methylquinoline (4A) was
used instead of compound 1D. LCMS-ESI.sup.+ (m/z): 284.2, 286.2
(M+H).sup.+.
Step 2.
[0766] Preparation of 8-(4-chlorophenyl)-6-methylquinolin-7-ol
(4C): Compound 4C was prepared following the procedure used to
prepare compound 1C of Example 1, except that
8-(4-chlorophenyl)-7-methoxy-6-methylquinoline (4B) was used
instead of compound 1B. LCMS-ESI.sup.+ (m/z): 270.2, 272.2
(M+H).sup.+.
Step 3.
[0767] Preparation of 8-(4-chlorophenyl)-6-methylquinolin-7-yl
trifluoromethanesulfonate (4D): Compound 4D was prepared following
the procedure used to prepare compound 1F of example 1, except that
8-(4-chloro-phenyl)-6-methylquinolin-7-ol (4C) was used instead of
compound 1E. LCMS-ESI.sup.+ (m/z): 402.0, 403.9 (M+H).sup.+.
Step 4.
[0768] Preparation of 8-(4-chlorophenyl)-6-methyl-7-vinylquinoline
(4E): Compound 4E was prepared following the procedure used to
prepare compound 1G of Example 1, except that
8-(4-chlorophenyl)-6-methylquinolin-7-yl trifluoromethanesulfonate
(4D) was used instead of compound 1F. LCMS-ESI.sup.+ (m/z): 280.2,
282.2 (M+H).sup.+.
Step 5.
[0769] Preparation of
(S)-1-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)ethane-1,2-diol
(4F): Compound 4F was prepared following the procedure used to
prepare compound 1H of Example 1, except that
8-(4-chlorophenyl)-6-methyl-7-vinyl-quinoline (4E) was used instead
of compound 1G. LCMS-ESI.sup.+ (m/z): 314.1, 316.1 (M+H).sup.+.
Step 6.
[0770] Preparation of
(S)-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)-2-hydroxyethyl
pivalate (4G): Compound 4G was prepared following the procedure
used to prepare compound 1I of example 1, except that
(S)-1-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)ethane-1,2-diol
(4F) was used instead of compound 1H. LCMS-ESI.sup.+ (m/z): 398.2,
400.2 (M+H).sup.+.
Step 7.
[0771] Preparation of
(S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)ethyl
pivalate (4I): Compound 4H was prepared following the procedure
used to prepare compound IJ of example 1, except that
(S)-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)-2-hydroxyethyl
pivalate (4G) was used instead of compound 1I.
[0772] LCMS-ESI.sup.+ (m/z): 454.3, 456.3 (M+H).sup.+.
Step 8.
[0773] Preparation of
(S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)ethanol
(4): Compound 41 was prepared following the procedure used to
prepare compound 1K of Example 1, except that
(S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)ethyl
pivalate (411) was used instead of compound 1J. LCMS-ESI.sup.+
(m/z): 370.2, 372.1 (M+H).sup.+.
Example 5
Preparation of
(S)-2-tert-butoxy-2-((S)-5-(2,4-dichlorophenyl)-2,7-dimethylquinolin-6-yl-
)acetic acid (5J)
##STR00124## ##STR00125##
[0775] To a stirred solution of (S)-ethyl
2-tert-butoxy-2-((S)-5-(2,4-dichlorophenyl)-2,7-dimethylquinolin-6-ypacet-
ate (510 (15 mg as TFA salt, 0.027 mmol) in THF and methanol (3
mL/1 mL) was added 1 M NaOH solution (1 mL, excess) at 0.degree. C.
The mixture was stirred at 50.degree. C. for 4 hours and diluted
with water. The mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried and concentrated in
vacuo. The obtained residue was purified by Prep-HPLC to provide
the desired isomer of 5J as a TFA salt (11 mg, 77%). .sup.1H-NMR
300 MHz, (CD.sub.3OD) .delta. 8.14 (d, 1H), 8.03 (s, 1H), 7.74 (d,
1H), 7.72 (d, 1H), 7.52 (dd, 1H), 7.25 (d, 1H), 5.36 (s, 1H), 2.96
(s, 3H), 2.90 (s, 3H), 1.11 (s, 9H); LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.23H.sub.24Cl.sub.2NO.sub.3: 433.3.
Found: 432.1, 434.1.
[0776] The (S,R) isomer of 5J was obtained using the same procedure
described above except that the (S,R) isomer of 5I was used in the
reaction. .sup.1H-NMR 300 MHz, (CD.sub.3OD) .delta. 8.18 (d, 1H),
7.99 (s, 1H), 7.80 (d, 1H), 7.77 (d, 1H), 7.73 (d, 1H), 7.66-7.62
(m 1H), 5.17 (s, 1H), 2.95 (s, 3H), 2.80 (s, 3H), 1.05 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.23H.sub.24Cl.sub.2NO.sub.3: 433.3. Found: 432.1, 434.1
Preparation of (S)-ethyl
2-tert-butoxy-2-((S)-5-(2,4-dichlorophenyl)-2,7-dimethylquinolin-6-ypacet-
ate (5I)
Step 1.
[0777] Preparation of 5-bromo-2,7-dimethylquinolin-6-yl
trifluoromethanesulfonate (5A): Compound 5A was prepared following
the procedure used to prepare compound 1F of Example 1, except that
5-bromo-2,7-dimethylquinolin-6-ol (2C) was used instead of compound
1E. LCMS-ESr (m/z): 383.9, 385.9 (M+14).sup.+.
Step 2.
[0778] Preparation of 5-bromo-2,7-dimethyl-6-vinylquinoline (5B):
PdCl.sub.2(PPh.sub.3).sub.2 (207 mg, 0.30 mmol) was added to a
mixture of 5-bromo-2,7-dimethylquinolin-6-yl
trifluoromethanesulfonate (5A) (1.13 g, 2.95 mmol),
tributyl(vinyl)stannane (0.95 mL, 3.25 mmol) and lithium chloride
(375 mg, 8.85 mmol) in DMF (30 mL). The reaction mixture was
flushed with argon, heated at 80.degree. C. for 4 hours, and then
the volatile component was removed in vacuo. The residue was
dissolved in ethyl acetate (200 mL), washed with NaHCO.sub.3
solution, water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The obtained residue was purified by
flash chromatography to provide 5B (678 mg, 88%). LCMS-ESI.sup.+
(m/z): 262.1, 264.1 (M+H).sup.+.
Step 3.
[0779] Preparation of
(S)-1-(5-bromo-2,7-dimethylquinolin-6-yDethane-1,2-diol (5C):
Compound 5C was prepared following the procedure used to prepare
compound 1H of Example 1, except that
5-bromo-2,7-dimethyl-6-vinylquinoline (5B) was used instead of
compound 1G. LCMS-ESI.sup.+ (m/z): 296.1, 298.1 (M+H).sup.+.
Step 4.
[0780] Preparation of
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-hydroxyethyl pivalate
(5D): Compound 5D was prepared following the procedure used to
prepare compound 1I of Example 1, except that
(S)-1-(5-bromo-2,7-dimethylquinolin-6-yl)ethane-1,2-diol (5C) was
used instead of compound 1H. LCMS-ESI.sup.+ (m/z): 380.2, 382.2
(M+H).sup.+.
Step 5.
[0781] Preparation of
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl
pivalate (5E): Compound 5E was prepared following the procedure
used to prepare compound 1J of Example 1, except that
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-hydroxyethyl pivalate
(5D) was used instead compound 1I. LCMS-ESI.sup.+ (m/z): 436.2,
438.2 (M+H).sup.+.
Step 6.
[0782] Preparation of
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethanol
(5F): Compound 5F was prepared following the procedure used to
prepare compound 1K of Example 1, except that
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl
pivalate (5E) was used instead of compound 1J. LCMS-ESI.sup.+
(m/z): 352.2, 354.2 (M+H).sup.+.
Step 7.
[0783] Preparation of
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic acid
(5G): Compound 5G was prepared following the procedure used to
prepare compound 1L of Example 1, except that
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethanol (5F)
was used instead of compound 1K. LCMS-ESI.sup.+ (m/z): 366.1, 368.1
(M+H).sup.+.
Step 8.
[0784] Preparation of (S)-ethyl
2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H): To
a stirred solution of
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic acid
(5G) (180 mg, 0.49 mmol) in DMF (15 mL) was added cesium carbonate
(321 mg, 0.98 mmol) at 0.degree. C. After being stirred for 10 min
iodoethane (0.059 mL, 0.74 mmol) was added. The mixture was stirred
at room temperature for 2 hours and quenched by the slow addition
of a NaHCO.sub.3 solution. The mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried and
concentrated. The residue was purified by column chromatography to
give the pure product 5H (168 mg, 87%). LCMS-ESI.sup.+ (m/z):
394.1, 396.1 (M+H).sup.+.
Step 9.
[0785] Preparation of (S)-ethyl
2-tert-butoxy-2-((S)-5-(2,4-dichlorophenyl)-2,7-dimethylquinolin-6-ypacet-
ate (5I): Pd.sub.2(dba).sub.3 (3.5 mg, 0.006 mmol) was added to a
mixture of (S)-ethyl
2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H) (24
mg, 0.061 mmol), 2,4-dichlorophenylboronic acid (23 mg, 0.12 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl ("Sphos", 5 mg,
0.012 mmol) and K.sub.3PO.sub.4 (39 mg, 0.18 mmol) in toluene (1.5
mL). The reaction mixture was flushed with argon, heated at
110.degree. C. for 16 hours, and then the volatile component was
removed in vacuo. The residue was dissolved in ethyl acetate (100
mL), washed with NaHCO.sub.3 solution, water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The obtained
residue was purified by prep-HPLC to provide two isomers of 51 as
white solids. Each was obtained as a TFA salt (desired (S,R)
enantiomer: 18 mg, 53%).
[0786] LCMS-ESI.sup.+ (m/z): 460.2, 462.2 (M+H).sup.+.
Example 6
Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-
-dimethylquinolin-6-yl)acetic acid (6D)
##STR00126##
[0788] (S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-2,7-dimethylquinolin-6-yl)acetic acid (6D) was
prepared following the procedure used to prepare compound 1L of
Example 1 except that
(2S)-2-tert-butoxy-2-(5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-2,7-dimethylquinolin-6-yl)ethanol (6C) was used
instead of compound 1K. .sup.1H-NMR 300 MHz, (CD.sub.3OD) .delta.
8.59 (d, 1H), 8.05 (s, 1H), 7.94 (d, 1H), 7.65 (d, 1H), 7.54 (d,
1H), 7.48 (d, 1H), 7.27 (d, 1H), 5.25 (s, 1H), 4.70-4.55 (m, 2H),
3.52-3.45 (m, 2H), 2.90 (s, 3H), 0.91 (s, 9H); LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.28H.sub.29N.sub.2O.sub.4: 457.5.
Found: 457.1.
Preparation of (2S)-2-tert-butoxy-2-(5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-2,7-dimethylquinolin-6-yl)ethanol (6C)
Step 1.
[0789] Preparation of
(2S)-2-tert-butoxy-2-(5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-di-
methylquinolin-6-yl)ethyl pivalate (6B): Pd(PPh.sub.3).sub.4 (4 mg,
0.0037 mmol) was added to a mixture
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl
pivalate (5E) (16 mg, 0.037 mmol),
2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride
(6A) (23 mg, 0.073 mmol) and K.sub.2CO.sub.3 (0.083 mL 2 M in
water, 1.66 mmol) in 1,2-dimethoxyethane (2 mL). The reaction
mixture was flushed with nitrogen, microwaved at 120.degree. C. for
90 min and the volatile component was removed in vacuo. The residue
was dissolved in ethyl acetate (50 mL), washed with NaHCO.sub.3
solution, water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The obtained residue was purified by
prep-HPLC to provide 6B as a white solid (4 mg as TFA salt, 18%).
LCMS-ESI.sup.+ (m/z): 527.3 (M+H).sup.+.
Step 2.
[0790] Preparation of
(2S)-2-tert-butoxy-2-(5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-di-
methylquinolin-6-yl)ethanol (6C): Compound 6C was prepared
following the procedure used to prepare compound 1K of Example 1
except that
(2S)-2-tert-butoxy-2-(5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-di-
methylquinolin-6-yDethyl pivalate (6B) was used instead of compound
1J. LCMS-ESI.sup.+ (m/z): 433.3 (M+H).sup.+.
Example 7
Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)acetic acid (7J)
##STR00127## ##STR00128##
[0792]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl-
)quinolin-6-yl)acetic acid (7J) was prepared following the
procedure used to prepare compound 1L of Example 1 except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethanol (71) was used instead of compound 1K. .sup.1H-NMR
300 MHz, (CD.sub.3OD) .delta. 8.01 (s, 1H), 7.95 (d, 1H), 7.71 (d,
1H), 7.65-7.55 (m, 2H), 7.35 (d, 1H), 5.24 (s, 1H), 2.71 (s, 3H),
0.99 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.23H.sub.22ClF.sub.3NO.sub.3: 452.9. Found: 452.1, 454.1.
Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethanol (7I)
Step 1.
[0793] Preparation of
5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-ol (7B): Compound 7B
was prepared following the procedure used to prepare compound 1C of
Example 1, except that
5-bromo-6-methoxy-7-methyl-2-(trifluoromethyl)quinoline (7A) was
used instead of compound 1B. LCMS-ESI.sup.+ (m/z): 306.1, 308.1
(M+H).sup.+.
Step 2.
[0794] Preparation of
5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl
trifluoromethanesulfonate (7C): Compound 7C was prepared following
the procedure used to prepare compound 1F of Example 1 except that
5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-ol (7B) was used
instead of compound 1E. LCMS-ESI.sup.+ (m/z): 437.8, 439.8
(M+H).sup.+.
Step 3.
[0795] Preparation of
5-bromo-7-methyl-2-(trifluoromethyl)-6-vinylquinoline (7D):
Compound 7D was prepared following the procedure used to prepare
compound 5B of Example 5, except that
5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl
trifluoromethanesulfonate (7C) was used instead of compound 5A.
LCMS-ESI.sup.+ (m/z): 316.1, 318.1 (M+H).sup.+.
Step 4.
[0796] Preparation of
(S)-1-(5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl)ethane-1,2-diol
(7E): Compound 7E was prepared following the procedure used to
prepare compound 1H of Example 1, except that
5-bromo-7-methyl-2-(trifluoromethyl)-6-vinylquinoline (7D) was used
instead 7 of compound 1G. LCMS-ESI.sup.+ (m/z): 350.1, 352.1
(M+H).sup.+.
Step 5.
[0797] Preparation of
(S)-2-(5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl)-2-hydroxyethyl
pivalate (7F): Compound 7F was prepared following the procedure
used to prepare compound 1I of Example 1 except that
(S)-1-(5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl)ethane-1,2-diol
(7E) was used instead of compound 1H.
Step 6.
[0798] Preparation of
(S)-2-(5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl)-2-tert-butoxyet-
hyl pivalate (7G): Compound 7G was prepared following the procedure
used to prepare compound 1J of Example 1 except
(S)-2-(5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl)-2-hydroxyethyl
pivalate (7F) was used instead of compound H. LCMS-ESI.sup.+ (m/z):
490.2, 492.2 (M+H).sup.+.
Step 7.
[0799] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethyl pivalate (7H): Compound 7H was prepared following
the procedure used to prepare compound 1E of Example 1 except that
(S)-2-(5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl)-2-tert-butoxyet-
hyl pivalate (7G) was used instead of compound 1D. LCMS-ESI.sup.+
(m/z): 522.2, 524.2 (M+H).sup.+.
Step 8.
[0800] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethanol (71): Following the procedure used to prepare
compound 1K of Example 1, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethyl pivalate (711) was used instead of compound 1J.
LCMS-ESI.sup.+ (m/z): 438.2, 440.2 (M+H).sup.+.
Example 8
Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)acetic acid (8L)
##STR00129## ##STR00130##
[0802] A stock solution of periodic acid/chromium trioxide was
prepared according to WO 99/52850 by dissolving periodic acid (11.4
g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet
acetonitrile (0.75% H.sub.2O) to a volume of 114 mL. This stock
solution (0.40 mL) was added to a solution of
(S)-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin--
2(1H)-one (8K, 4.4 mg) in wet acetonitrile (1.5 mL, 0.75% H.sub.2O)
at 0.degree. C. After stirring for 60 min at 0.degree. C., the
reaction was quenched with 1.5 M K.sub.2HPO.sub.4 solution and
extracted with ethyl acetate (2.times.). The combined organic layer
was washed with 1:1 brine/H.sub.2O (2.times.), saturated
NaHSO.sub.3/brine, and was dried (MgSO.sub.4). Concentration and
purification by prep-HPLC gave
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)acetic acid (8L) (2 mg). .sup.1H-NMR 300 MHz, (CD.sub.3OD)
7.56-7.53 (3H, m), 7.35 (1H, d, J=9.7 Hz), 7.28 (1H, d, J=8.2 Hz),
7.22 (1H, s), 6.43 (1H, d, J=9.8 Hz), 5.06 (1H, s), 2.55 (3H, s),
0.95 (9H, s). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.22H.sub.23ClNO.sub.4: 400.9. Found: 400.2;
[0803] LCMS-ESI.sup.- (m/z): [M-H].sup.- calcd for
C.sub.22H.sub.21ClNO.sub.4: 398.9. Found: 397.9.
Preparation of
(S)-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin--
2(1H)-one (8K)
Step 1.
[0804] Preparation of 4-methoxy-3-methylaniline (8B): To the
solution of 1-methoxy-2-methyl-4-nitrobenzene (10 g, 60 mmol) in
EtOH and EtOAc (250 mL, 3:2) was added 10% Pd/C (2 g). The mixture
was stirred for 24 h under one atmosphere of hydrogen. Celite was
added and the mixture was stirred for 10 min. The mixture was
filtered through a pad of celite. Concentration under reduced
pressure gave 4-methoxy-3-methylaniline (8B) (8.2 g).
LCMS-ESI.sup.+ (m/z): 138.2 (M+H).sup.+.
Step 2.
[0805] Preparation of 6-methoxy-7-methylquinoline (3B): To
4-methoxy-3-methylaniline (6.7 g) was added concentrated
H.sub.2SO.sub.4 (12.4 mL), followed by glycerin (21.1 g),
m-nitrobenzenesulfonic acid (6.53 g), H.sub.3BO.sub.3 (3.4 g) and
FeSO.sub.47H.sub.2O (3.2 g). The mixture was stirred at 140.degree.
C. for 1 h. The reaction was cooled to 25.degree. C., quenched with
ice-water and neutralized with 30% KOH. The mixture was extracted
with DCM (2.times.), and the combined extracts dried with
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was
purified by column chromatography (EtOAc) to give
6-methoxy-7-methylquinoline (4.3 g) LCMS-ESI.sup.+ (m/z): 174.1
(M+H).sup.+.
Step 3.
[0806] Preparation of 5-bromo-6-methoxy-7-methylquinoline (8C): To
the solution of 6-methoxy-7-methylquinoline (4.28 g, 24.6 mmol) in
50 mL of concentrated H.sub.2SO.sub.4 was added NBS (4.41 g, 14.6
mmol) at 15.degree. C., and the reaction was stirred at 15.degree.
C. for 3.5 hours. The reaction mixture was poured into ice-water
(600 mL). The aqueous mixture was adjusted with a 50% KOH solution
to pH -10, and then extracted with DCM (3.times.). The combined
extract was dried with sodium sulfate. Concentration under reduced
pressure gave 5-bromo-6-methoxy-7-methylquinoline (6.3 g).
LCMS-ESI.sup.+ (m/z): 252.1, 254.1 (M+H).sup.+.
Step 4.
[0807] Preparation of 5-bromo-7-methylquinolin-6-ol (3D): To the
solution of 5-bromo-6-methoxy-7-methylquinoline (6.5 g, 25.8 mmol)
in DCM (150 mL) was added BBr.sub.3 slowly (77.3 mL, 1.0 M in DCM,
77.3 mmol). The mixture was stirred for 3 hours and cooled to
0.degree. C. Methanol (40 mL) was added slowly and the mixture was
stirred for 20 minutes. The solvents were removed under reduced
pressure. The solid was dissolved in methanol (100 mL) and was
treated with 1.0 N sodium hydroxide solution (50 mL) (pH 12). The
mixture was stirred for 12 hours and acetic acid was added to
adjust pH to between 4-5. The mixture was filtered and washed with
water. The gray solid was dried under reduced pressure to give
5-bromo-7-methylquinolin-6-ol (5.0 g). LCMS-ESI.sup.+ (m/z): 238.2,
240.1 (M+H).sup.+, 236.1, 238.0 (M-H).
Step 5.
[0808] Preparation of 5-bromo-7-methylquinolin-6-yl
trifluoromethanesulfonate (8D): To the solution of
5-bromo-7-methylquinolin-6-ol (238 mg, 1.0 mmol) in dichloromethane
(10 mL) and pyridine (2 mL) was added Tf.sub.2O (0.34 mL, 2.0 mmol)
at -30.degree. C. The mixture was stirred and warmed to 0.degree.
C. over a period of 2 hours. The reaction was quenched with slow
addition of NaHCO.sub.3 solution. The mixture was extracted with
ethyl acetate. The organic layer was washed with brine, dried over
sodium sulfate and concentrated to give
5-bromo-7-methylquinolin-6-yl trifluoromethanesulfonate.
LCMS-ESI.sup.+ (m/z): 369.9, 371.9 (M+H).sup.+.
Step 6.
[0809] Preparation of 5-bromo-7-methyl-6-vinylquinoline (8E): A
mixture of 5-bromo-7-methylquinolin-6-yl trifluoromethanesulfonate
(230 mg, 0.62 mmol), tributyl(vinyl)stannane (200 .mu.L, 0.68
mmol), lithium chloride (78 mg, 1.86 mmol) and
PdCl.sub.2(PPh.sub.3).sub.2 (43 mg) in DMF (10 mL) was heated at
80.degree. C. for 16 hours, and then the volatile component was
removed in vacuo. The residue was dissolved in ethyl acetate (100
mL), washed with NaHCO.sub.3 solution, water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue
was purified by flash chromatography (hexanes/EtOAc) to provide
5-bromo-7-methyl-6-vinylquinoline (120 mg). LCMS-ESI.sup.+ (m/z):
248.2, 250.2 (M+H).sup.+.
Step 7.
[0810] Preparation of
(S)-1-(5-bromo-7-methylquinolin-6-yl)ethane-1,2-diol (8F):
AD-mix-.alpha. (0.7 g) was added to a mixed solvent of t-butanol
and water (2.5 mL/2.5 mL) and stirred at 25.degree. C. for 5 min,
cooled to 0.degree. C. The mixture was transferred to another flask
containing 5-bromo-7-methyl-6-vinylquinoline (120 mg) and stirred
at 0.degree. C. for 48 hours. The mixture was diluted with ethyl
acetate, washed with NaHCO.sub.3 solution, water and brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography (EtOAc) to
provide (S)-1-(5-bromo-7-methylquinolin-6-yl)ethane-1,2-diol (118
mg). LCMS-ESI.sup.+ (m/z): 282.1, 284.1 (M+H).sup.+.
Step 8.
[0811] Preparation of
(S)-2-(5-bromo-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate
(8G): To a stirred solution of
(S)-1-(5-bromo-7-methylquinolin-6-ypethane-1,2-diol (118 mg, 0.42
mmol) in dichloromethane (5 mL) and pyridine (1 mL) was added
trimethylacetyl chloride (100 .mu.L, 0.84 mmol) at 0.degree. C. The
mixture was stirred at room temperature for 12 hours, quenched with
slow addition of NaHCO.sub.3 solution. The mixture was extracted
with ethyl acetate. The organic layer was washed with brine, dried
over Na.sub.2SO.sub.4. Concentration gave the intermediate (124 mg)
m/z 366.1, 368.1 (M+H).sup.+. To the solution of above intermediate
(124 mg, 0.34 mmol) in t-butylacetate (3 mL) was added 70%
perchloric acid (67 uL, 1.1 mmol) at 25.degree. C. The mixture was
stirred at 25.degree. C. for 2 hours, quenched with slow addition
of NaHCO.sub.3 solution. The mixture was extracted with ethyl
acetate. The organic layer was washed with brine, dried and
concentrated in vacuo. The residue was purified by flash
chromatography (hexanes/EtOAc) to provide
(S)-2-(5-bromo-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate
(133 mg). LCMS-ESI.sup.+ (m/z): 422.1, 424.2 (M+H).sup.+.
Step 9.
[0812] Preparation of
(S)-2-(2-acetoxy-5-bromo-7-methylquinolin-6-yl)-2-tert-butoxyethyl
pivalate (8H): To the solution of
(S)-2-(5-bromo-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate
(130 mg, 0.31 mmol) in DCM (2 mL) was added mCPBA (70%, 95 mg, 0.39
mmol). The mixture was stirred for 12 hours. The mixture was
diluted with EtOAc, washed with saturated sodium bicarbonate
solution, water and brine, and dried over sodium sulfate.
Concentration under reduced pressure gave the intermediate N-oxide
(147 mg). LCMS-ESI.sup.+ (m/z): 438.2, 440.2 (M+H).sup.+. To the
above intermediate was added acetic anhydride (5 mL). The mixture
was heated at 140.degree. C. for 10 hours. The excess reagents were
removed under reduced pressure. The mixture was diluted with EtOAc,
washed with saturated sodium bicarbonate solution, water and brine,
and dried over sodium sulfate. Concentration gave
(S)-2-(2-acetoxy-5-bromo-7-methylquinolin-6-yl)-2-tert-butoxyethyl
pivalate (130 mg). LCMS-ESI.sup.+ (m/z): 480.0, 482.0
(M+H).sup.+.
Step 10.
[0813] Preparation of
(S)-2-(5-bromo-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethy-
l pivalate (81): To the solution of
(S)-2-(2-acetoxy-5-bromo-7-methylquinolin-6-yl)-2-tert-butoxyethyl
pivalate (130 mg) in ethanol (7.5 mL) was added aqueous methylamine
solution (0.5 mL, 50%). The mixture was heated at 78.degree. C. for
80 min. Concentration and purification gave
(S)-2-(5-bromo-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethy-
l pivalate (68 mg). LCMS-ESI.sup.+ (m/z): 438.2, 440.2
(M+H).sup.+.
Step 11.
[0814] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)ethyl pivalate (8J): The mixture of
(S)-2-(5-bromo-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethy-
l pivalate (34 mg, 0.078 mmol), Pd(PPh.sub.3).sub.4 (9 mg),
4-chlorophenylboronic acid (16 mg, 0.1 mmol), aqueous
K.sub.2CO.sub.3 solution (0.15 mL, 2 M, 0.3 mmol) in
1,2-dimethoxyethane (2 mL) was heated at 100.degree. C. for 90
minutes. The residue was diluted with ethyl acetate (100 mL),
washed with NaHCO.sub.3 solution, water and brine, dried over
Na.sub.2SO.sub.4. Concentration and purification gave
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)ethyl pivalate (22 mg). LCMS-ESI.sup.+ (m/z): 470.3
(M+H).sup.+.
Step 12.
[0815] Preparation of
(S)-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin--
2(1H)-one (8K): To the solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)ethyl pivalate (5.8 mg) in THF and methanol (1.5 mL/0.5 mL)
was added 1 M NaOH solution (0.6 mL). The mixture was stirred at
25.degree. C. for 16 hours, diluted with water. The mixture was
extracted with ethyl acetate. The organic layer was washed with
brine and dried over sodium sulfate. Concentration gave
(S)-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin--
2(1H)-one (4.4 mg). LCMS-ESI.sup.+ (m/z): 386.2 (M+H).sup.+.
Example 9
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methyl-
quinolin-6-yl)acetic acid (9)
##STR00131## ##STR00132##
[0817] Preparation of
(S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline
1-oxide: To a stirred solution of
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl
pivalate (5E) (118 mg, 0.31 mmol) in chloroform (5 mL) was added
mCPBA (209 mg, 77%, 0.93 mmol) at 0.degree. C. The mixture was
stirred at 0.degree. C. for 1 hour before quenched with NaHCO.sub.3
solution. The mixture was extracted with DCM (30 mL), washed with
NaHCO.sub.3 solution, water and brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The obtained residue was
purified by flash chromatography to provide the desired product (52
mg, 37%). LCMS-ESI.sup.+ (m/z): 452.1, 454.1 (M+H).sup.+.
[0818] Preparation of
(S)-2-(5-bromo-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)-2-tert-bu-
toxyethyl pivalate: To a stirred solution of
(S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline
1-oxide (25 mg, 0.055 mmol) in toluene (3 mL) was added
benzenesulfonyl chloride (0.06 mL, 0.24 mmol). The mixture was
stirred at 110.degree. C. for 16 hours, then cooled to room
temperature. Dimethylamine (2 mL 2 M solution in methanol, excess)
was added. The mixture was stirred at room temperature for 16 h,
then diluted in ethyl acetate (30 mL), washed with NaHCO.sub.3
solution, water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The obtained residue was purified by
HPLC to provide the desired product as a white solid (11 mg, 42%).
LCMS-ESI.sup.+ (m/z): 479.3, 481.3 (M+H).sup.+.
[0819] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-Aethyl pivalate: Pd(PPh.sub.3).sub.4 (2.5 mg, 0.002
mmol) was added to a mixture
(S)-2-(5-bromo-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)-2-tert-bu-
toxyethyl pivalate (11 mg, 0.023 mmol), 4-chlorophenylboronic acid
(7 mg, 0.046 mmol), K.sub.2CO.sub.3 (0.06 mL 2 M in water, 0.13
mmol) in 1,2-dimethoxyethane (1 mL). The reaction mixture was
flushed with nitrogen, heated at 110.degree. C. for 30 min under
microwave, and then the volatile component was removed in vacuo.
The residue was dissolved in ethyl acetate (100 mL), washed with
NaHCO.sub.3 solution, water and brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The obtained residue was
purified by HPLC to provide the desired product as a white solid
(5.6 mg, 48%). LCMS-ESI.sup.+ (m/z): 511.3, 513.3 (M+H).sup.+.
[0820] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)ethanol: To a stirred solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)ethyl pivalate (5.6 mg, 0.011 mmol) in THF and
methanol (1.5 mL/0.5 mL) was added 2 M NaOH solution (0.5 mL,
excess) at 0.degree. C. The mixture was stirred at 50.degree. C.
for 3 hours, diluted with water and the resulting mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried and concentrated in vacuo. The obtained residue was
purified by prep-HPLC to provide the desired product (3.0 mg, 64%).
LCMS-ESI.sup.+ (m/z): 427.3, 429.2 (M+H).sup.+.
[0821] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)acetic acid (9): A stock solution of periodic
acid/chromium trioxide was prepared according to WO 99/52850 by
dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide
(23 mg, 1.2 mol %) in wet acetonitrile (0.75% H.sub.2O) to a volume
of 114 mL. This stock solution (0.50 mL) was added to a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)ethanol (3 mg, 0.007 mmol) in wet acetonitrile (2.0
mL, 0.75% H.sub.2O) at 0.degree. C. Reaction mixture was stirred
for 30 minutes at 0.degree. C. and quenched with NaHCO.sub.3
solution. Ethyl acetate was added and organic layer separated and
washed with 1:1 brine/H.sub.2O (2.times.), then saturated
NaHSO.sub.3/brine. The organic layer was dried (MgSO.sub.4),
concentrated and purified by reverse phase HPLC to give the product
as TFA salt (2.5 mg, 81%). .sup.1H-NMR 300 MHz, (CD.sub.3OD)
.delta. 7.97 (s, 1H), 7.78 (d, 1H), 7.65-7.55 (m, 3H), 7.40-7.30
(m, 2H), 5.22 (s, 1H), 4.65 (s, 2H), 3.04 (s, 6H), 2.68 (s, 3H),
0.98 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.29ClN.sub.2O.sub.3: 441.9. Found: 441.2, 443.3.
Example 10
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methylamino)methyl)qu-
inolin-6-yl)acetic acid (10)
##STR00133## ##STR00134##
[0823] Preparation of
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethyl
pivalate: Pd(PPh.sub.3).sub.4 (69 mg, 0.06 mmol) was added to a
mixture
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl
pivalate (5E) (325 mg, 0.75 mmol), 4-chlorophenylboronic acid (175
mg, 1.1 mmol), K.sub.2CO.sub.3 (1.3 mL 2 M in water, 2.6 mmol) in
1,2-dimethoxyethane (10 mL). The reaction mixture was flushed with
nitrogen, heated at 110.degree. C. for 30 min under microwave, and
then the volatile component was removed in vacuo. The residue was
dissolved in ethyl acetate (100 mL), washed with NaHCO.sub.3
solution, water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The obtained residue was purified by
flash chromatography to provide the desired product (256 mg, 73%).
LCMS-ESI.sup.+ (m/z): 468.3, 469.3 (M+H).sup.+.
[0824] Preparation of
(S)-6-(1-tert-Butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethy-
lquinoline 1-oxide: Following the procedure used to prepare
compound
(S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline
1-oxide of Example 9, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)ethyl
pivalate was used instead of
(S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl
pivalate. LCMS-ESI.sup.+ (m/z): 484.3, 486.3 (M+H).sup.+.
[0825] Preparation of
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methylamino)methyl)q-
uinolin-6-yl)ethyl pivalate: Following the procedure used to
prepare compound
(S)-2-(5-bromo-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)--
2-tert-butoxyethyl pivalate of Example 9, except that
(S)-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethy-
lquinoline 1-oxide was used instead of
(S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline
1-oxide, and methylamine solution was used instead of
N,N-dimethylamine solution. LCMS-ESI.sup.+ (m/z): 497.3, 499.3
(M+H).sup.+.
[0826] Preparation of
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methylamino)methyl)q-
uinolin-6-yl)ethanol: Following the procedure used to prepare
compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)ethanol of Example 9, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methylamino)methyl)q-
uinolin-6-yl)ethyl pivalate was used instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)ethyl pivalate. LCMS-ESI.sup.+ (m/z): 413.3, 415.3
(M+H).sup.+.
[0827] Preparation of
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methylamino)methyl)q-
uinolin-6-yl)acetic acid (10): Following the procedure used to
prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl-
)-7-methylquinolin-6-yl)acetic acid (9) of Example 9, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methylamino)methyl)q-
uinolin-6-yl)ethanol was used instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)ethanol. .sup.1H-NMR 300 MHz, (CD.sub.3OD)
.delta.7.95 (s, 1H), 7.74 (d, 1H), 7.65-7.55 (m, 3H), 7.35-7.28 (m,
2H), 5.22 (s, 1H), 4.51 (s, 2H), 2.88 (s, 3H), 2.67 (s, 3H), 0.98
(s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.24H.sub.27ClN.sub.2O.sub.3: 427.9. Found: 427.2, 429.2.
Example 11
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)q-
uinolin-6-yl)acetic acid: (11)
##STR00135##
[0829] Preparation of
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethypq-
uinolin-6-yl)ethyl pivalate:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethypq-
uinolin-6-yl)ethyl pivalate was prepared following the procedure
used to prepare compound
(S)-2-(5-bromo-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)-2-tert-bu-
toxyethyl pivalate of Example 9, except that
(S)-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethy-
lquinoline 1-oxide was used instead of
(S)-5-bromo-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-2,7-dimethylquinoline
1-oxide, and piperidine was used instead of N,N-dimethylamine
solution. LCMS-ESI.sup.+ (m/z): 551.3, 553.3 (M+H).sup.+.
[0830] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)-
quinolin-6-yl)ethanol:
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)-
quinolin-6-yl)ethanol was prepared following the procedure used to
prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl-
)-7-methylquinolin-6-yl)ethanol of Example 9, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)-
quinolin-6-yl)ethyl pivalate was used instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)ethyl pivalate. LCMS-ESI.sup.+ (m/z): 467.4, 469.3
(M+H).sup.+.
[0831] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)-
quinolin-6-yl)acetic acid (11):
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethypq-
uinolin-6-yl)acetic acid was prepared following the procedure used
to prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)acetic acid (9) of Example 9, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(piperidin-1-ylmethyl)-
quinolin-6-yl)ethanol was used instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)ethanol. .sup.1H-NMR 300 MHz, (CD.sub.3OD) .delta.
7.97 (s, 1H), 7.77 (d, 1H), 7.65-7.58 (m, 3H), 7.40-7.30 (m, 2H),
5.22 (s, 1H), 4.61 (s, 2H), 3.60-3.20 (m, 4H), 2.69 (s, 3H),
2.00-1.90 (m, 4H), 1.80-1.65 (m, 2H), 0.98 (s, 9H); LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.28H.sub.33ClN.sub.2O.sub.3:
482.0;
[0832] Found: 481.3, 483.3.
Example 12
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(methoxycarbonyl)-7-methylquinol-
in-6-yl)acetic acid: (12)
##STR00136##
[0834] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-7-methylquinoli-
n-6-yl)ethanol: To a stirred solution of
(S)-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethy-
lquinoline 1-oxide (compound of Example 10) (14 mg, 0.03 mmol) in
toluene (2 mL) was added benzenesulfonyl chloride (0.04 mL, 0.29
mmol). The mixture was stirred at 110.degree. C. for 16 hours, then
cooled to room temperature. Sodium methoxide (1 mL 25% solution in
methanol, excess) was added. The mixture was stirred at room
temperature for 16 hours, then water (1 mL) was added. The mixture
was stirred at 60.degree. C. for 1 hour. The reaction mixture was
diluted in ethyl acetate (30 mL), washed with NaHCO.sub.3 solution,
water and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The obtained residue was purified by HPLC to
provide the desired product as TFA salt (4.8 mg, 33%).
LCMS-ESI.sup.+ (m/z): 414.2, 416.2 (M+H).sup.+.
[0835] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxycarbonyl)-7-methylquino-
lin-6-yl)acetic acid (12): A stock solution of periodic
acid/chromium trioxide was prepared according to WO 99/52850 by
dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide
(23 mg, 1.2 mol %) in wet acetonitrile (0.75% H.sub.2O) to a volume
of 114 mL. This stock solution (0.50 mL) was added to a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-7-methylquinoli-
n-6-yl)ethanol (4.8 mg, 0.01 mmol) in wet acetonitrile (2.0 mL,
0.75% H.sub.2O) at 0.degree. C. The reaction mixture was stirred
for 1 hour at 0.degree. C. and quenched with NaHCO.sub.3 solution.
Ethyl acetate was added and the organic layer separated and washed
with 1:1 brine/H.sub.2O (2.times.), then saturated
NaHSO.sub.3/brine. The organic layer was dried (MgSO.sub.4) and
concentrated and purified by reverse phase HPLC to give the product
as TFA salt (2.7 mg, 61%). .sup.1H-NMR 300 MHz, (CD.sub.3OD)
.delta. 8.10-8.00 (m, 2H), 7.90 (d, 1H), 7.70-7.57 (m, 3H), 7.35
(d, 1H), 5.23 (s, 1H), 4.03 (s, 3H), 2.70 (s, 3H), 0.98 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.24H.sub.25ClNO.sub.5: 442.9. Found: 442.2, 444.2.
Example 13
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(ethoxycarbonyl)-7-methylquinoli-
n-6-yl)acetic acid (13)
##STR00137##
[0837] Preparation of
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(ethoxymethyl)-7-methylquinolin-
-6-yl)ethanol:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(ethoxymethyl)-7-methylquinolin-
-6-yl)ethanol was prepared following the procedure used to prepare
compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-7-meth-
ylquinolin-6-yl)ethanol of Example 12, except that sodium ethoxide
in ethanol solution was used instead of sodium methoxide in
methanol solution. LCMS-ESI.sup.+ (m/z): 428.2, 430.2
(M+H).sup.+.
[0838] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(ethoxycarbonyl)-7-methylquinol-
in-6-yl)acetic acid (13):
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(ethoxycarbonyl)-7-methylquinol-
in-6-yl)acetic acid was prepared following the procedure used to
prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxycarbonyl)-7-me-
thylquinolin-6-yl)acetic acid of Example 12, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(ethoxymethyl)-7-methylquinolin-
-6-yl)ethanol was used instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-7-methylquinoli-
n-6-yl)ethanol. .sup.1H-NMR 300 MHz, (CD.sub.3OD) .delta.8.10-8.00
(m, 2H), 7.90 (d, 1H), 7.70-7.57 (m, 3H), 7.35 (d, 1H), 5.23 (s,
1H), 4.50 (q, 2H), 2.70 (s, 3H), 1.46 (t, 3H) 0.98 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.26ClNO.sub.5: 456.9. Found: 456.2, 458.2.
Example 14
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenypamino)
methyl)quinolin-6-yl)acetic acid (14)
##STR00138## ##STR00139##
[0840] Preparation of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yDacetate:
Pd(PPh.sub.3).sub.4 (68 mg, 0.06 mmol) was added to a mixture of
(S)-ethyl
2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H)
(230 mg, 0.59 mmol) and 4-chlorophenylboronic acid (183 mg, 1.17
mmol), K.sub.2CO.sub.3 (1.0 mL 2 M in water, 2.06 mmol) in
1,2-dimethoxyethane (8 mL). The reaction mixture was flushed with
nitrogen, heated at 110.degree. C. for 30 min under microwave, and
then the volatile component was removed in vacuo. The residue was
dissolved in ethyl acetate (100 mL), washed with NaHCO.sub.3
solution, water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The obtained residue was purified by
HPLC to provide the desired product (200 mg, 80%). LCMS-ESI.sup.+
(m/z): 426.2, 428.2 (M+H).sup.+.
[0841] Preparation of
(S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethyl-
quinoline 1-oxide: To a stirred solution of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-ypacetate
(100 mg, 0.25 mmol) in dichloromethane (5 mL) was added a solution
of mCPBA (114 mg, 77%, 0.51 mmol) in DCM (2 mL) at 0.degree. C. The
mixture was stirred at 0.degree. C. for 1 hour before quenched with
NaHCO.sub.3 solution. The mixture was extracted with DCM (30 mL),
washed with NaHCO.sub.3 solution, water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The obtained
residue was purified by flash chromatography to provide the desired
product (104 mg, 94%). LCMS-ESI.sup.+ (m/z): 442.2, 444.3
(M+H).sup.+.
[0842] Preparation of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)
amino)methyl)quinolin-6-yl)acetate: To a stirred solution of
(S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethyl-
quinoline 1-oxide (13 mg, 0.029 mmol) in toluene (2 mL) was added
benzenesulfonyl chloride (0.2 mL, excess). The mixture was stirred
at 80.degree. C. for 1 hour, then cooled to room temperature.
N-methylaniline (0.2 mL, excess) and K.sub.2CO.sub.3 (250 mg,
excess) were added. The mixture was stirred at 60.degree. C. for 16
h, then diluted in ethyl acetate (30 mL), washed with NaHCO.sub.3
solution, water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The obtained residue was purified by
flash chromatography to provide the desired product (12 mg, 78%).
LCMS-ESI.sup.+ (m/z): 531.3, 533.2 (M+H).sup.+.
[0843] Preparation of
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)
methyl)quinolin-6-yl)acetic acid (14): To a stirred solution of
(S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenypamino)methy-
pquinolin-6-ypacetate (12 mg, 0.023 mmol) in THF and methanol (2
mL/1 mL) was added 2 M NaOH solution (0.5 mL, excess) at 0.degree.
C. The mixture was stirred at 50.degree. C. for 3 hours, diluted
with water. The mixture was extracted with ethyl acetate. The
organic layer was washed with brine, dried and concentrated in
vacuo. The obtained residue was purified by prep-HPLC to provide
the desired product as TFA salt (9.0 mg, 65%). .sup.1H-NMR 300 MHz,
(CD.sub.3OD). .delta.8.21 (d, 1H), 8.07 (s, 1H), 7.70-7.55 (m, 4H),
7.40-7.32 (m, 1H), 7.26-7.18 (m, 2H), 6.90-6.75 (m, 3H), 5.24 (s,
1H), 5.01 (s, 2H), 3.17 (s, 3H), 2.77 (s, 3H), 0.98 (s, 9H);
LCMS-EST.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.30H.sub.32ClN.sub.2O.sub.3: 504.0. Found: 503.3, 505.2.
Example 15
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenypamino)
methyl)quinolin-6-yl)acetic acid (15)
##STR00140##
[0845] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(ethoxymethyl)-7-methylquinolin-
-6-yl)acetic acid (15): To a stirred solution of
(S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethyl-
quinoline 1-oxide (compound of Example 14) (12 mg, 0.027 mmol) in
toluene (2 mL) was added benzenesulfonyl chloride (0.2 mL, excess).
The mixture was stirred at 80.degree. C. for 1 hour, then cooled to
room temperature. Sodium ethoxide (0.5 mL 21% ethanol solution,
excess) was added. The mixture was stirred at 60.degree. C. for 16
h. Water (1 mL) was added, and the mixture was stirred at
60.degree. C. for another 4 hours. The reaction mixture was diluted
in ethyl acetate (30 mL), washed with NaHCO.sub.3 solution, water
and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The obtained residue was purified by prep-HPLC to provide
the desired product as TFA salt (3.0 mg, 21%). .sup.1H-NMR 300 MHz,
(CD.sub.3OD) .delta. 8.19 (d, 1H), 8.06 (s, 1H), 7.73 (d, 1H),
7.70-7.60 (m, 3H), 7.40-7.35 (m, 1H), 5.24 (s, 1H), 4.95 (s, 2H),
3.75 (q, 2H), 2.75 (s, 3H), 1.32 (t, 3H), 0.98 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.29ClNO.sub.4: 442.9. Found: 442.2, 444.2.
Example 16
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)-7-methylquin-
olin-6-yl)acetic acid: (16)
##STR00141## ##STR00142##
[0847] Preparation of (S)-ethyl
2-(2-(acetoxymethyl)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-but-
oxyacetate: Acetic anhydride was added to a flask containing
(S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethyl-
quinoline 1-oxide (compound of Example 14) (42 mg, 0.095 mmol). The
mixture was stirred at 80.degree. C. for 1 hour. Acetic anhydride
was removed under vacuum. The residue was dissolved in ethyl
acetate (50 mL). The organic layer was washed with NaHCO.sub.3
solution and water, dried and concentrated in vacuo. The obtained
residue was used for next step reaction without purification.
LCMS-ESI.sup.+ (m/z): 484.2, 486.2 (M+H).sup.+.
[0848] Preparation of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(hydroxymethyl)-7-methylquinolin-6--
ypacetate: To a stirred solution of (S)-ethyl
2-(2-(acetoxymethyl)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-but-
oxyacetate (0.095 mmol) in methanol (2 mL) was added 2 M
K.sub.2CO.sub.3 (0.5 mL, excess) at room temperature. The mixture
was stirred at room temperature for 1 hour, diluted with water. The
mixture was extracted with ethyl acetate. The organic layer was
washed with brine, dried and concentrated in vacuo. The obtained
residue was purified by flash chromatography to provide the desired
product (26 mg, 62%). LCMS-ESI.sup.+ (m/z): 442.2, 444.2
(M+H).sup.+.
[0849] Preparation of
(S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-7-methylquin-
oline-2-carboxylic acid:
(S)-6-(1-tert-Butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-7-methylquin-
oline-2-carboxylic acid was prepared following the procedure used
to prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)acetic acid of Example 9, except that (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(hydroxymethyl)-7-methylquinolin-6--
yl)acetate was used instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methy-
lquinolin-6-yl)ethanol. LCMS-ESI.sup.+ (m/z): 456.2, 458.2
(M+H).sup.+.
[0850] Preparation of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)-7-methylquinoli-
n-6-ypacetate: To a stirred solution of
(S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-7-methylquin-
oline-2-carboxylic acid (14 mg, 0.032 mmol), dimethylamine HCl salt
(13 mg, 0.16 mmol) and DIPEA (0.056 mL, 0.32 mmol) in DMF (1 mL)
was added HATU (61 mg, 0.16 mmol) at 0.degree. C. The mixture was
stirred for 2 hours at ambient temperature. The mixture was diluted
with ethyl acetate (30 mL) and washed with water and brine, then
dried over Na.sub.2SO.sub.4. Concentration and purification by
column chromatography provided the product (7 mg, 45%).
LCMS-ESI.sup.+ (m/z): 483.2, 485.3 (M+H).sup.+.
[0851] Preparation of
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)-7-methylqui-
nolin-6-yl)acetic acid (16):
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)-7-methylqui-
nolin-6-yl)acetic acid was prepared following the procedure used to
prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)
methyl)quinolin-6-yl)acetic acid of Example 14, except that
(S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)-7-methylquinoli-
n-6-yDacetate was used instead of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)meth-
yl) quinolin-6-yl)acetate. .sup.1H-NMR 300 MHz, (CD.sub.3OD)
.delta. 7.91 (s, 1H), 7.87 (d, 1H), 7.65-7.58 (m, 3H), 7.50 (d,
1H), 7.40-7.32 (m, 1H), 5.23 (s, 1H), 3.18 (s, 3H), 3.05 (s, 3H),
2.69 (s, 3H), 0.99 (s, 9H);
[0852] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.28ClN.sub.2O.sub.4: 455.9. Found: 455.2, 457.2.
Example 17
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamoy-
l)quinolin-6-yl)acetic acid: (17)
##STR00143##
[0854] Preparation of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamoyl)
quinolin-6-yl)acetate: (S)-Ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamoyl)
quinolin-6-yl)acetate was prepared following the procedure used to
prepare compound (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)-7-methylquinoli-
n-6-yl)acetate of Example 16, except that N-methylaniline was used
instead of dimethylamine HCl salt. LCMS-ER.sup.+ (m/z): 545.2,
547.2 (M+H).sup.+.
[0855] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamo-
yl)quinolin-6-yl)acetic acid (17):
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamo-
yl)quinolin-6-yl)acetic acid was prepared following the procedure
used to prepare compound
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenypamino)
methyl)quinolin-6-yl)acetic acid of Example 14, except that
(S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamoyl)q-
uinolin-6-yl)acetate was used instead of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)meth-
yl) quinolin-6-yl)acetate. .sup.1H-NMR 300 MHz, (CD.sub.3OD)
.delta. 7.80-7.50 (m, 6H), 7.40-7.10 (m, 6H), 5.16 (s, 1H), 3.54
(s, 3H), 2.62 (s, 3H), 0.95 (s, 9H); LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.30H.sub.30ClN.sub.2O.sub.4: 518.0.
Found: 517.2, 519.2.
Example 19
2-(5-(Biphenyl-4-yl)-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic
acid (19)
##STR00144##
[0857] Preparation of ethyl
2-(5-(biphenyl-4-yl)-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate:
Ethyl
2-(5-(biphenyl-4-yl)-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetat-
e was prepared following the procedure used to prepare compound
(S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-ypacetate
of Example 14, except that biphenyl-4-ylboronic acid was used
instead of 4-chlorophenylboronic acid. LCMS-ESI.sup.+ (m/z): 468.3
(M+H).sup.+.
[0858] Preparation of
2-(5-(biphenyl-4-yl)-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic
acid (19):
2-(5-(Biphenyl-4-yl)-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetic
acid was prepared following the procedure used to prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)
methyl)quinolin-6-yl)acetic acid of Example 14, except that ethyl
2-(5-(biphenyl-4-yl)-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate
was used instead of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)meth-
yl) quinolin-6-yl)acetate. .sup.1H-NMR 300 MHz, (CD.sub.3OD) 8.40
(d, 1H), 7.96 (s, 1H), 7.95-7.90 (m, 2H), 7.70-7.60 (m, 4H),
7.55-7.40 (m, 4H), 5.39 (s, 1H), 2.96 (s, 3H), 2.80 (s, 3H), 0.98
(s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.29H.sub.30NO.sub.3: 440.6. Found: 440.2.
Example 20
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-((-
dimethylamino)methyl)-7-methylquinolin-6-yl)acetic acid (20)
##STR00145## ##STR00146##
[0860] Preparation of
(S)-5-bromo-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-2,7-dimethylquinoline
1-oxide: To a stirred solution of (S)-ethyl
2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H)
(248 mg, 0.63 mmol) in dichloromethane (8 mL) was added a solution
of mCPBA (283 mg, 77%, 1.26 mmol) in DCM (5 mL) at 0.degree. C. The
mixture was stirred at 0.degree. C. for 1 hour before quenched with
NaHCO.sub.3 solution. The mixture was extracted with DCM (30 mL),
washed with NaHCO.sub.3 solution, water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The obtained
residue was purified by flash chromatography to provide the desired
product (212 mg, 82%). LCMS-ESI.sup.+ (m/z): 410.2, 412.2
(M+H).sup.+.
[0861] Preparation
(R)-6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(2,3-dihydropyrano[4,3,2--
de]quinolin-7-yl)-2,7-dimethylquinoline 1-oxide:
Pd(PPh.sub.3).sub.4 (36 mg, 0.03 mmol) was added to a mixture
(S)-5-bromo-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-2,7-dimethylquinoline
1-oxide (86 mg, 0.21 mmol),
2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride
(105 mg, 0.42 mmol), K.sub.2CO.sub.3 (0.47 mL 2 M in water, 0.95
mmol) in N,N-dimethylacetamide (3 mL). The reaction mixture was
flushed with nitrogen, heated at 90.degree. C. for 16 hours. The
mixture was dissolved in ethyl acetate (50 mL), washed with
NaHCO.sub.3 solution, water and brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The obtained residue was
purified by HPLC to provide the desired product (87 mg, 69%).
LCMS-ESI.sup.+ (m/z): 501.2 (M+H).sup.+.
[0862] Preparation of (S)-ethyl
2-((R)-2-(acetoxymethyl)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethylquinolin-6-yl)-2-tert-butoxyacetate: (S)-Ethyl
2-((R)-2-(acetoxymethyl)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethylquinolin-6-yl)-2-tert-butoxyacetate was prepared following the
procedure used to prepare compound (S)-ethyl
2-(2-(acetoxymethyl)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-but-
oxy-acetate of Example 16, except that
(R)-6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(2,3-dihydropyrano[4,3,2--
de]quinolin-7-yl)-2,7-dimethylquinoline 1-oxide was used instead of
2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline
1-oxide. LCMS-ESI.sup.+ (m/z): 543.1 (M+H).sup.+.
[0863] Preparation of (S)-ethyl
2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(hydr-
oxymethyl)-7-methylquinolin-6-ypacetate: (S)-Ethyl
2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(hydr-
oxymethyl)-7-methylquinolin-6-ypacetate was prepared following the
procedure used to prepare compound (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(hydroxymethyl)-7-methylquinolin-6--
yl)acetate of Example 16, except that (S)-ethyl
2-((R)-2-(acetoxymethyl)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethylquinolin-6-yl)-2-tert-butoxyacetate was used instead of
(S)-ethyl
2-(2-(acetoxymethyl)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-but-
oxyacetate. LCMS-ESI.sup.+ (m/z): 501.2 (M+H).sup.+.
[0864] Preparation of (S)-ethyl
2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-((dim-
ethylamino)methyl)-7-methylquinolin-6-yl)acetate: To a stirred
solution of (S)-ethyl
2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-2-(hydroxymethyl)-7-methylquinolin-6-ypacetate (15 mg, 0.03
mmol) and DIPEA (0.013 mL, 0.075 mmol) in dichloromethane (1 mL)
was added methanesulfonyl chloride (6.8 mg, 0.06 mmol) at 0.degree.
C. The mixture was stirred at room temperature for 3 hours before
the addition of N,N-dimethylamine in methanol (0.5 mL 2 M, excess).
The mixture was stirred at room temperature for another 1 h, then
diluted in ethyl acetate (30 mL), washed with NaHCO.sub.3 solution,
water and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The obtained residue was purified by HPLC to
provide the desired product as TFA salt (18 mg, 97%).
LCMS-ESI.sup.+ (m/z): 528.3 (M+H).sup.+.
[0865] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
(dimethylamino)methyl)-7-methylquinolin-6-yl)acetic acid (20):
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
(dimethylamino)methyl)-7-methylquinolin-6-yl)acetic acid was
prepared following the procedure used to prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)
methyl)quinolin-6-yl)acetic acid of Example 14, except that
(S)-ethyl
2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-((dim-
ethylamino)methyl)-7-methylquinolin-6-yl)acetate was used instead
of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)-
amino)methyl) quinolin-6-yl)acetate. .sup.1H-NMR 300 MHz,
(CD.sub.3OD) .delta. 8.70 (d, 1H), 8.20 (s, 1H), 7.83-7.75 (m, 2H),
7.51 (d, 1H), 7.42 (d, 1H), 7.29 (d, 1H), 5.26 (s, 1H), 5.75-5.68
(m, 2H), 4.66 (s, 2H), 3.64 (t, 2H), 3.05 (s, 6H), 2.85 (s, 3H),
0.93 (s, 9H); LCMS-ESI.sup.+ (m/z):
[0866] [M+14].sup.+ calcd for C.sub.30H.sub.34N.sub.3O.sub.4:
500.6. Found: 500.2.
Example 21
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(h-
ydroxymethyl)-7-methylquinolin-6-yl)acetic acid (21)
##STR00147##
[0868] Preparation
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
hydroxymethyl)-7-methylquinolin-6-yl)acetic acid (21): To a stirred
solution of (S)-ethyl
2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(hydr-
oxymethyl)-7-methylquinolin-6-ypacetate (compound of Example 20)
(10 mg, 0.02 mmol) in THF and methanol (2 mL/1 mL) was added 2 M
NaOH solution (0.5 mL, excess). The mixture was stirred at
50.degree. C. for 3 hours, diluted with water. The mixture was
extracted with ethyl acetate. The organic layer was washed with
brine, dried and concentrated in vacuo. The obtained residue was
purified by prep-HPLC to provide the desired product as TFA salt
(9.0 mg, 79%). .sup.1H-NMR 300 MHz, (CD.sub.3OD) 8.66 (d, 1H), 8.27
(s, 1H), 7.94 (d, 1H), 7.67 (d, 1H), 7.70-7.60 (m, 2H), 7.37 (d,
1H), 5.26 (s, 1H), 5.06 (s, 2H), 4.75-4.65 (m, 2H), 3.57 (t, 2H),
2.90 (s, 3H), 0.93 (s, 91-1);
[0869] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.28H.sub.29N.sub.2O.sub.4: 473.5. Found: 473.1.
Example 22
(R)-6-((S)-tert-butoxy(carboxy)methyl)-5-(2,3-dihydropyrano[4,3,2-de]quino-
lin-7-yl)-2,7-dimethylquinoline 1-oxide (22)
##STR00148##
[0871]
(R)-6-((S)-tert-Butoxy(carboxy)methyl)-5-(2,3-dihydropyrano[4,3,2-d-
e]quinolin-7-yl)-2,7-dimethylquinoline 1-oxide (22) was prepared
following the procedure used to prepare compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
hydroxymethyl)-7-methylquinolin-6-yl)acetic acid of Example 21,
except that
(R)-6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(2,3-dihydropyrano[4-
,3,2-de]quinolin-7-yl)-2,7-dimethylquinoline 1-oxide was used
instead of (S)-ethyl
2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-2-(hydroxymethyl)-7-methylquinolin-6-ypacetate. .sup.1H-NMR 300
MHz, (CD.sub.3OD) .delta. 8.78-8.70 (m, 2H), 7.85 (d, 1H), 7.78 (d,
Hi), 7.44 (d, 1H), 7.35 (d, 1H), 7.11 (d, 1H), 5.23 (s, 1H),
5.75-5.65 (m, 2H), 3.65 (t, 2H), 2.88 (s, 3H), 2.70 (s, 3H), 0.93
(s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.28H.sub.29N.sub.2O.sub.5: 473.5. Found: 473.2.
Example 23
(S)-2-tert-Butoxy-2-((S)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7--
dimethylquinolin-6-yl)acetic acid (23)
##STR00149##
[0873] Preparation of (S)-ethyl
2-tert-butoxy-2-((S)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-dim-
ethylquinolin-6-ypacetate: Pd(PPh.sub.3).sub.4 (103 mg, 0.09 mmol)
was added to a mixture (S)-ethyl
2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H)
(350 mg, 0.89 mmol),
2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride
(447 mg, 1.78 mmol), K.sub.2CO.sub.3 (2.0 mL 2 M in water, 4.0
mmol) in N,N-dimethylacetamide (10 mL). The reaction mixture was
flushed with nitrogen, heated at 90.degree. C. for 16 h. The
mixture was dissolved in ethyl acetate (150 mL), washed with
NaHCO.sub.3 solution, water and brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The obtained residue was
purified by HPLC to provide the desired product (407 mg, 43%).
LCMS-ESI.sup.+ (m/z): 485.2 (M+H).sup.+.
[0874] Preparation of
(S)-2-tert-butoxy-2-((S)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-
-dimethylquinolin-6-yl)acetic acid (23):
(S)-2-tert-Butoxy-2-((S)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2,7-
-dimethylquinolin-6-yl)acetic acid was prepared following the
procedure used to prepare compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
hydroxymethyl)-7-methylquinolin-6-yl)acetic acid of Example 21,
except (S)-ethyl
2-tert-butoxy-2-((S)-5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-2,7-dimethylquinolin-6-yDacetate was used instead of
(S)-ethyl 2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate.
.sup.1H-NMR 300 MHz, (CD.sub.3OD) .delta. 8.51 (d, 2H), 8.02-7.95
(m, 3H), 7.54 (d, 1H), 7.36 (d, 1H), 7.28 (d, 1H), 5.28 (s, 1H),
4.60 (t, 2H), 3.43 (t, 2H), 2.93 (s, 3H), 2.83 (s, 3H), 0.72 (s,
9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.28H.sub.28N.sub.2O.sub.4: 457.5. Found: 457.1.
Example 24
(S)-6-(tert-Butoxy(carboxy)methyl)-5-(4-chlorophenyl)-7-methylquinoline-2--
carboxylic acid (24)
##STR00150##
[0876] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)-
methyl)quinolin-6-yl)ethyl pivalate:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)-
methyl)quinolin-6-yl)ethyl pivalate was prepared following the
procedure used to prepare compound (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)meth-
yl)quinolin-6-yl)acetate of Example 14, except that
(S)-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethy-
lquinoline 1-oxide was used instead of
(S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethyl-
quinoline 1-oxide. LCMS-ESI.sup.+ (m/z): 573.3, 575.4
(M+H).sup.+.
[0877] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)-
methyl)quinolin-6-yl)ethanol:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)-
methyl)quinolin-6-yl)ethanol was prepared following the procedure
used to prepare compound
S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(h-
ydroxymethyl)-7-methylquinolin-6-yl)acetic acid of Example 21,
except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)-
methyl)quinolin-6-yl)ethyl pivalate was used instead of (S)-ethyl
2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(hydr-
oxymethyl)-7-methylquinolin-6-ypacetate. LCMS-ESI.sup.+ (m/z):
489.3, 491.3 (M+H).sup.+.
[0878] Preparation of
(S)-6-(tert-butoxy(carboxy)methyl)-5-(4-chlorophenyl)-7-methylquinoline-2-
-carboxylic acid (24):
(S)-6-(tert-Butoxy(carboxy)methyl)-5-(4-chlorophenyl)-7-methylquinoline-2-
-carboxylic acid was prepared following the procedure used to
prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxycarbonyl)-7-me-
thylquinolin-6-yl)acetic acid of Example 12, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)-
methyl) quinolin-6-yl)ethanol was used instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-7-methylquinoli-
n-6-yl)ethanol. .sup.1H-NMR 300 MHz, (CD.sub.3OD). .delta.8.15-8.05
(m, 2H), 7.93 (d, 1H), 7.70-7.60 (m, 3H), 7.40-7.35 (m, 1H), 5.24
(s, 1H), 2.70 (s, 3H), 0.99 (s, 9H); LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.23H.sub.23ClNO.sub.5: 428.9. Found:
428.1, 430.1.
Example 25
(S)-2-tert-butoxy-2-(5-cyclohexenyl-2-((dimethylamino)methyl)-7-methylquin-
olin-6-yl)acetic acid (25)
##STR00151## ##STR00152##
[0880] Preparation of
(S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-cyclohexenyl-2,7-dimethylquin-
oline 1-oxide: Pd(PPh.sub.3).sub.4 (6 mg, 0.006 mmol) was added to
a mixture
(S)-5-bromo-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-2,7-dimethylqui-
noline 1-oxide (compound of Example 20) (20 mg, 0.05 mmol),
cyclohexenylboronic acid (12 mg, 0.1 mmol), K.sub.2CO.sub.3 (0.09
mL 2 M in water, 0.17 mmol) in 1,2-dimethoxyethane (1 mL). The
reaction mixture was flushed with nitrogen, heated at 85.degree. C.
for overnight, and then the volatile component was removed in
vacuo. The residue was dissolved in ethyl acetate (30 mL), washed
with NaHCO.sub.3 solution, water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The obtained
residue was purified by HPLC to provide the desired product (17 mg,
68%). LCMS-ESI.sup.+ (m/z): 412.3 (M+H).sup.+.
[0881] Preparation of (S)-ethyl
2-(2-(acetoxymethyl)-5-cyclohexenyl-7-methylquinolin-6-yl)-2-tert-butoxya-
cetate: (S)-Ethyl
2-(2-(acetoxymethyl)-5-cyclohexenyl-7-methylquinolin-6-yl)-2-tert-butoxya-
cetate was prepared following the procedure used to prepare
compound (S)-ethyl
2-(2-(acetoxymethyl)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)--
2-tert-butoxyacetate of Example 16, except that
(S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-cyclohexenyl-2,7-dimethylquin-
oline 1-oxide was used instead of
2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline
1-oxide. LCMS-ESI.sup.+ (m/z): 454.3 (M+H).sup.+.
[0882] Preparation of (S)-ethyl
2-tert-butoxy-2-(5-cyclohexenyl-2-(hydroxymethyl)-7-methylquinolin-6-ypac-
etate: (S)-Ethyl
2-tert-butoxy-2-(5-cyclohexenyl-2-(hydroxymethyl)-7-methylquinolin-6-yDac-
etate was prepared following the procedure used to prepare compound
(S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(hydroxymethyl)-7-methylq-
uinolin-6-yl)acetate of Example 16, except that (S)-ethyl
2-(2-(acetoxymethyl)-5-cyclohexenyl-7-methylquinolin-6-yl)-2-tert-butoxya-
cetate was used instead of (S)-ethyl
2-(2-(acetoxymethyl)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-but-
oxyacetate. LCMS-ESI.sup.+ (m/z): 412.3 (M+H).sup.+.
[0883] Preparation of (S)-ethyl
2-tert-butoxy-2-(5-cyclohexenyl-2-((dimethylamino)methyl)-7-methylquinoli-
n-6-yl)acetate: (S)-Ethyl
2-tert-Butoxy-2-(5-cyclohexenyl-2-((dimethylamino)methyl)-7-methylquinoli-
n-6-ypacetate was prepared following the procedure used to prepare
compound (S)-ethyl
2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-((dim-
ethylamino)methyl)-7-methylquinolin-6-ypacetate of Example 20
except that (S)-ethyl
2-tert-butoxy-2-(5-cyclohexenyl-2-(hydroxymethyl)-7-methylquino-
lin-6-yl)acetate was used instead of (S)-ethyl
2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(hydr-
oxymethyl)-7-methylquinolin-6-ypacetate. LCMS-ESI.sup.+ (m/z):
439.4 (M+H).sup.+.
[0884] Preparation of
(S)-2-tert-butoxy-2-(5-cyclohexenyl-2-((dimethylamino)methyl)-7-methylqui-
nolin-6-yl)acetic acid (25):
(S)-2-tert-Butoxy-2-(5-cyclohexenyl-2-((dimethylamino)methyl)-7-methylqui-
nolin-6-yl)acetic acid was prepared following the procedure used to
prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)
methyl)quinolin-6-yl)acetic acid of Example 14, except that
(S)-ethyl 2-tert-butoxy-2-(5-cyclohexenyl-2-((dimethylamino)
methyl)-7-methylquinolin-6-yl)acetate was used instead of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)meth-
yl)quinolin-6-yl)acetate. .sup.1H-NMR 300 MHz, (CD.sub.3OD)
8.40-8.30 (m, 1H), 7.85-7.78 (m, 1H), 7.42 (d, 1H), 6.04, 5.70 (br,
br, 1H), 5.80, 5.64 (s, s, 1H), 4.65 (s, 2H), 3.04 (s, 6H),
2.68-2.56 (m, 4H), 2.40-1.80 (m, 6H), 1.30-1.20 (m, 9H);
LCMS-ESI.sup.+ (m/z): [M-1-11].sup.+ calcd for
C.sub.25H.sub.34N.sub.2O.sub.3: 411.6. Found: 411.3.
Example 26
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)acet-
ic acid (26)
##STR00153## ##STR00154##
[0886] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy) quinolin-6-yl)ethyl pivalate: To a stirred solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)ethyl pivalate (8J) (200 mg, 0.43 mmol) in dichloromethane
(10 mL) and pyridine (0.35 mL) was added Tf.sub.2O (0.1 mL, 0.87
mmol) at -78.degree. C. The temperature was slowly raised to
0.degree. C. The mixture was stirred at 0.degree. C. for 2 hours,
quenched with slowly addition of NaHCO.sub.3 solution. The mixture
was extracted with ethyl acetate. The organic layer was washed with
brine, dried and concentrated to provide a brown colored solid. The
obtained residue was purified by flash chromatography to provide
the desired product (200 mg, 77%). LCMS-ESI.sup.+ (m/z): 602.0,
604.0 (M+H).sup.+.
[0887] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)eth-
yl pivalate: PdCl.sub.2(PPh.sub.3).sub.2 (3 mg, 0.004 mmol) was
added to
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate (25 mg, 0.04 mmol),
tributyl-vinyl-stannane (0.024 mL, 0.08 mmol) and lithium chloride
(7 mg, 0.16 mmol) in DMF (2 mL). The reaction mixture was flushed
with nitrogen, heated at 90.degree. C. for 16 hours, and then the
volatile component was removed in vacuo. The residue was dissolved
in ethyl acetate (100 mL), washed with NaHCO.sub.3 solution, water
and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The obtained residue was purified by HPLC to provide the
desired product as TFA salt (14 mg, 59%). LCMS-ESI.sup.+ (m/z):
480.3, 482.3 (M+H).sup.+.
[0888] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)eth-
anol: To a stirred solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)eth-
yl pivalate TFA salt (14 mg, 0.024 mmol) in THF and methanol (3
mL/1 mL) was added 1 M NaOH solution (0.5 mL, excess). The mixture
was stirred at 0.degree. C. for 6 hours and diluted with water. The
resulting mixture was extracted with ethyl acetate. The organic
layer was washed with brine, dried and concentrated in vacuo. The
obtained residue was used in the next reaction without
purification. LCMS-ESI.sup.+ (m/z): 396.2, 398.2 (M+H).sup.+.
[0889] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)eth-
anol: A balloon filled with hydrogen was connected to a degassed
mixture of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)-
ethanol (9 mg, 0.024 mmol) and Rhodium on activated alumina (2 mg,
cat.) in ethanol. The mixture was stirred at room temperature for 2
hours, filtered and concentrated to dry. The obtained residue was
used on next step reaction without purification. LCMS-ESI.sup.+
(m/z): 398.2, 400.2 (M+H).sup.+.
[0890] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)ace-
tic acid (26):
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)ace-
tic acid was prepared following the procedure used to prepare
compound
tert-butoxy-[7-chloro-5-(4-chloro-phenyl)-2-methyl-quinolin-6-yl]-acetic
acid of Example 1, except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)eth-
anol was used instead
2-tert-butoxy-2-[7-chloro-5-(4-chloro-phenyl)-2-methyl-quinolin-6-yl]etha-
nol. .sup.1H-NMR 300 MHz, (CD.sub.3OD) .delta. 8.31 (d, 1H), 7.98
(s, 1H), 7.76 (d, 1H), 7.70-7.60 (m, 3H), 7.42-7.35 (m, 1H), 5.25
(s, 1H), 3.21 (q, 2H), 2.78 (s, 3H), 1.48 (t, 3H), 0.98 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.24H.sub.27ClNO.sub.3: 412.9. Found: 412.2, 414.2.
Example 27
(S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic
acid (27)
##STR00155##
[0892] Preparation of
(S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethyl
pivalate: Pd(PPh.sub.3).sub.4 (4.6 mg, 0.004 mmol) was added to a
mixture
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (25 mg,
0.04 mmol), 4-chlorophenylboronic acid (13 mg, 0.08 mmol),
Na.sub.2CO.sub.3 (0.14 mL 1 M in water, 0.14 mmol) in
1,2-dimethoxyethane (2 mL). The reaction mixture was flushed with
nitrogen, heated at 90.degree. C. for 16 hours, and then the
volatile component was removed in vacuo. The residue was dissolved
in ethyl acetate (100 mL), washed with NaHCO.sub.3 solution, water
and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The obtained residue was purified by HPLC to provide the
desired product as a TFA salt (15 mg, 55%). LCMS-ESI.sup.+ (m/z):
564.3, 566.3, 568.3 (M+H).sup.+.
[0893] Preparation of
(S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethano-
l:
(S)-2-(2,5-Bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyetha-
nol was prepared following the procedure used to prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)eth-
anol (compound of Example 26), except that
(S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethyl
pivalate was used instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)eth-
yl pivalate. LCMS-ESI.sup.+ (m/z): 480.2, 482.2, 484.2
(M+H).sup.+.
[0894] Preparation of
(S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic
acid (27):
(S)-2-(2,5-Bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic
acid was prepared following the procedure used to prepare compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)ace-
tic acid (compound of Example 26), except that
(S)-2-(2,5-bis(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethano-
l was used instead
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)eth-
anol. .sup.1H-NMR 300 MHz, (CD.sub.3OD) .delta. 8.15-8.02 (m, 4H),
7.98 (d, 1H), 7.70-7.60 (m, 5H), 7.38 (d, 1H), 5.24 (s, 1H), 2.74
(s, 3H), 0.98 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.28H.sub.25Cl.sub.2NO.sub.3: 495.4. Found: 494.2, 496.2,
498.2.
Example 28
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7-methylquinolin-6-y-
l)acetic acid (28)
##STR00156##
[0896] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7-methylquinolin-6--
yl)ethyl pivalate: Pd(PPh.sub.3).sub.4 (4.7 mg, 0.004 mmol) was
added to a mixture
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluorometh-
ylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26)
(25 mg, 0.04 mmol), cyclopropylboronic acid (7 mg, 0.08 mmol), KF
(8 mg, 0.14) and NaBr (6 mg, 0.06 mmol) in toluene (2 mL) One drop
of water was added to the mixture. The reaction mixture was flushed
with nitrogen, heated at 90.degree. C. for 16 hours, and then the
volatile component was removed in vacuo. The residue was dissolved
in ethyl acetate (100 mL), washed with NaHCO.sub.3 solution, water
and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The obtained residue was purified by HPLC to provide the
desired product as a TFA salt (11 mg, 47%). LCMS-ESI.sup.+ (m/z):
494.3, 496.3 (M+H).sup.+.
[0897] Preparation of
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7-methylquinolin-6--
yl)ethanol:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7-methylquinolin-6--
yl)ethanol was prepared following the procedure used to prepare
compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)eth-
anol, (compound of Example 26) except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7-methylquinolin-6--
yl)ethyl pivalate was used instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-vinylquinolin-6-yl)eth-
yl pivalate. LCMS-ESI.sup.+ (m/z): 410.3, 412.2 (M+H).sup.+.
[0898] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7-methylquinolin-6--
yl)acetic acid (28):
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7-methylquinolin-6--
yl)acetic acid was prepared following the procedure used to prepare
compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-
-6-yl)acetic acid (compound of Example 26) except
that(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-cyclopropyl-7-methylquinoli-
n-6-yl)ethanol was used instead
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-ethyl-7-methylquinolin-6-yl)eth-
anol. .sup.1H-NMR 300 MHz, (CD.sub.3OD) .delta. 8.19 (d, 1H), 7.96
(s, 1H), 7.70-7.58 (m, 3H, 7.40-7.30 (m, 214), 5.23 (s, 1H), 2.77
(s, 3H), 2.58-2.48 (m, 114), 1.65-1.55 (m, 2H), 1.42-1.36 (m, 2H),
0.98 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.26ClNO.sub.3: 424.9. Found: 424.2, 426.2.
Example 29
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl-
)acetic acid (29)
##STR00157##
[0900] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethyl pivalate: A mixture of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate (12 mg, prepared as in Example
26) and morpholine (0.2 mL) in DME was heated at 80.degree. C. for
12 hours. Concentration in vacuo gave
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethyl pivalate (15 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd
for C.sub.31H.sub.40ClN.sub.2O.sub.4: 539.3. Found: 539.4.
[0901] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethanol: To the solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethyl pivalate (15 mg) in THF/MeOH (1 mL/1 mL) was added sodium
hydroxide solution (1.0 N, 1 mL). The mixture was heated at
50.degree. C. for 16 hours and was diluted with water. The aqueous
was extracted with ethyl acetate, and the organic phase was washed
with brine, and dried over sodium sulfate. Concentration under
reduced pressure gave
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethanol (10 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.26H.sub.32ClN.sub.2O.sub.3: 454.2. Found: 455.3.
[0902] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)acetic acid (29): A stock solution of periodic acid/chromium
trioxide was prepared according to WO 99/52850 by dissolving
periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2
mol %) in wet acetonitrile (0.75% H.sub.2O) to a volume of 114 mL.
This stock solution (0.40 mL) was added to a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethanol (10 mg) in wet acetonitrile (1.5 mL, 0.75% H.sub.2O) at
0.degree. C. The reaction mixture was stirred for 30 minutes at
0.degree. C. Filtration and purification by reverse phase HPLC
(0.1% TFA/CH3CN-0.1% TFA/H2O) gave
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)acetic acid (7.2 mg). .sup.1H-NMR 400 MHz, (CD.sub.3OD) .delta.
7.76 (m, 2H), 7.62 (m, 3H), 7.30 (m, 2H), 5.14 (s, 1H), 3.89 (m,
8H), 2.66 (s, 3H), 0.97 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calcd for C.sub.26H.sub.30ClN.sub.2O.sub.4: 469.2. Found: 469.3;
LCMS-ESI.sup.- (m/z): [M-H].sup.- calcd for
C.sub.26H.sub.28ClN.sub.2O.sub.4: 467.2 Found: 467.0.
Example 30
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(cyclopropylamino)-7-methylquino-
lin-6-yl)acetic acid (30)
##STR00158##
[0904]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(cyclopropylamino)-7-meth-
ylquinolin-6-yl)acetic acid (30) was prepared in a similar manner
as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoqui-
nolin-6-yl)acetic acid of Example 29 except using cyclopropylamine
instead of morpholine. .sup.1H-NMR 400 MHz, (CD.sub.3OD) .delta.
7.82 (m, 1H), 7.61 (m, 4H), 7.30 (d, J=7.6 Hz, 1H), 6.80 (m, 1H),
5.12 (s, 1H), 2.90 (m, 1H), 2.67 (s, 3H), 1.10 (m, 2H), 0.97 (s,
9H), 0.81 (m, 2H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.28ClN.sub.2O.sub.3: 439.2. Found: 439.2;
LCMS-ESI.sup.- (m/z): [M-H].sup.- calcd for
C.sub.25H.sub.26ClN.sub.2O.sub.3: 437.2. Found: 437.0;
Example 31
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methylamino)quinolin-6-
-yl)acetic acid (31)
##STR00159##
[0906]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methylamino)qui-
nolin-6-yl)acetic acid (31) was prepared in a similar manner as
compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)acetic acid of Example 29 except using methylamine instead of
morpholine. .sup.1H-NMR 400 MHz, (CD.sub.3OD) .delta.7.7 (m, 1H),
7.58 (m, 4H), 7.30 (d, J=8.4 Hz, 1H), 6.82 (m, 1H), 5.11 (s, 1H),
3.19 (s, 3H), 2.64 (s, 3H), 0.97 (s, 9H); LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.23H.sub.26ClN.sub.2O.sub.3: 413.2.
Found: 413.2.
Example 32
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(dimethylamino)-7-methylquinolin-
-6-yl)acetic acid (32)
##STR00160##
[0908]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(dimethylamino)-7-methylq-
uinolin-6-yl)acetic acid (32) was prepared in a similar manner as
compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)acetic acid of Example 29 except using dimethylamine instead of
morpholine. .sup.1H-NMR 400 MHz, (CD.sub.3OD) .delta. 7.79 (s, 1H),
7.71 (d, J=10 Hz, 1H), 7.60 (m, 3H), 7.31 (d, J=8 Hz, 1H), 7.16 (d,
J=10.4 Hz, 1H), 5.13 (s, 1H), 3.42 (s, 6H), 2.66 (s, 3H), 0.97 (s,
9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.24H.sub.28ClN.sub.2O.sub.3: 427.2. Found: 427.2; LCMS-ESI
(m/z): [M--H].sup.- calcd for C.sub.24H.sub.26ClN.sub.2O.sub.3:
425.2. Found: 425.0.
Example 33
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-4-ylmethylamin-
o)quinolin-6-yl)acetic acid (33)
##STR00161##
[0910]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-4-ylmet-
hylamino)quinolin-6-yl)acetic acid (33) was prepared in a similar
manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)acetic acid of Example 29 except using pyridin-4-ylmethanamime
instead of morpholine. .sup.1H-NMR 400 MHz, (CD.sub.3OD) .delta.
8.67 (m, 2H), 7.72 (m, 3H), 7.60 (m, 4H), 7.31 (d, J=8.4 Hz, 1H),
6.97 (d, J=9.2 Hz, 1H), 5.12 (s, 1H), 5.0 (s, 2H), 2.64 (s, 3H),
0.96 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.28H.sub.29ClN.sub.3O.sub.3: 490.2.
[0911] Found: 490.2; LCMS-ESI (m/z): [M-H].sup.- calcd for
C.sub.28H.sub.27ClN.sub.3O.sub.3: 488.2. Found: 488.0.
Example 34
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(2-morpholinoethylamino-
) quinolin-6-yl)acetic acid (34)
##STR00162##
[0913]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(2-morpholinoeth-
ylamino)quinolin-6-yl)acetic acid (34) was prepared in a similar
manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoqui-
nolin-6-yl)acetic acid of Example 29 except using
2-morpholinoethanamine instead of morpholine. .sup.1H-NMR 400 MHz,
(CD.sub.3OD) .delta. 7.73-7.55 (m, 5H), 7.29 (d, J=8 Hz, 1H), 6.90
(m, 1H), 5.12 (s, 1H), 4.05-3.81 (m, 6H), 3.45-3.35 (m, 6H), 2.65
(s, 3H), 0.97 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.28H.sub.35ClN.sub.3O.sub.4: 512.2. Found: 512.2;
LCMS-ESI.sup.- (m/z): [M-H].sup.- calcd for
C.sub.28H.sub.33ClN.sub.3O.sub.4: 510.2. Found: 510.1.
Example 35
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(3-(2-methoxyethoxy)propylamino)-
-7-methylquinolin-6-yl)acetic acid (35)
##STR00163##
[0915]
((S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(3-(2-methoxyethoxy)prop-
ylamino)-7-methylquinolin-6-yl)acetic acid (35) was prepared in a
similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)acetic acid of Example 29 except using
3-(2-methoxyethoxy)propan-1-amine instead of morpholine.
.sup.1H-NMR 400 MHz, (CD.sub.3OD) .delta. 7.7-7.55 (m, 5H), 7.30
(d, J=8 Hz, 1H), 6.85 (m, 1H), 5.11 (s, 1H), 3.7-3.5 (m, 8H), 3.35
(s, 3H), 2.65 (s, 3H), 2.05 (m, 2H), 0.97 (s, 9H); LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.28H.sub.36ClN.sub.2O.sub.5:
515.2. Found: 515.3; LCMS-ESI.sup.- (m/z): [M-H].sup.- calcd for
C.sub.28H.sub.34ClN.sub.2O.sub.5: 513.2. Found: 513.0.
Example 36
(S)-2-tert-butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,2-de]quinol-
in-7-yl)-7-methylquinolin-6-yl)acetic acid (36)
##STR00164## ##STR00165##
[0917] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate:
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (800 mg) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)ethyl pivalate of Example 29 except using
2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride
instead of 4-chlorophenylboronic acid. LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.32H.sub.37N.sub.2O.sub.5: 529.3. Found:
529.0.
[0918] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate:
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
was prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate of Example 29 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)ethyl pivalate LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.33H.sub.36F.sub.3N.sub.2O.sub.7S: 661.2. Found: 661.0.
[0919] Preparation of
(S)-2-tert-butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,2-de]quino-
lin-7-yl)-7-methylquinolin-6-yl)ethyl pivalate: To a suspension of
copper(I) cyanide (40 mg, 0.44 mmol) in THF (1 mL) at -40.degree.
C. was added tert-butyllithium (0.48 mL, 1.7 N, 0.82 mmol) slowly.
The mixture was stirred for 5 minutes, and a solution of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
(40 mg, 0.06 mmol) in THF (0.5 mL) was added dropwise. The reaction
mixture was kept at -45 to -35.degree. C. for 4 hours, and warmed
to 25.degree. C. slowly and stirred for 12 hours. The reaction was
quenched with water, and extracted with ethyl acetate. The organic
layer was washed with brine, and dried with sodium sulfate.
Concentration and purification by flash column chromatography
(hexanes/EtOAc) gave
(S)-2-tert-butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,2-de]quino-
lin-7-yl)-7-methylquinolin-6-yl)ethyl pivalate (14 mg).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.36H.sub.45N.sub.2O.sub.4: 569.3. Found: 569.4.
[0920] Preparation of
(S)-2-tert-butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,2-de]quino-
lin-7-yl)-7-methylquinolin-6-yl)ethanol:
(S)-2-tert-Butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,2-de]quino-
lin-7-yl)-7-methylquinolin-6-yl)ethanol (13 mg) was prepared in a
similar manner as compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol of Example 29, except
using(S)-2-tert-butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,2-de]-
quinolin-7-yl)-7-methylquinolin-6-yl)ethyl pivalate instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethyl pivalate. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.37N.sub.2O.sub.3: 485.2. Found: 485.1.
[0921] Preparation of
(S)-2-tert-butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,2-de]quino-
lin-7-yl)-7-methylquinolin-6-yl)acetic acid (36):
(S)-2-tert-Butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,2-de]quino-
lin-7-yl)-7-methylquinolin-6-yl)acetic acid (11.6 mg) was prepared
in a similar manner as compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)acetic acid of Example 29, except using
(S)-2-tert-butoxy-2-((R)-2-tert-butyl-5-(2,3-dihydropyrano[4,3,2-de]quino-
lin-7-yl)-7-methylquinolin-6-yl)ethanol instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethanol. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.62 (d, J=4.8
Hz, 1H), 8.27 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.71 (d, J=8 Hz,
1H), 7.66 (d, J=8.8 Hz, 1H), 7.59 (d, J=5.2 Hz, 1H), 7.33 (d, J=7.6
Hz, 1 H), 5.26 (s, 1H), 4.66 (m, 2H), 3.55 (m, 2H), 2.89 (s, 3H),
1.54 (s, 9H), 0.92 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd
for C.sub.31H.sub.35N.sub.2O.sub.4: 499.2. Found: 499.2;
LCMS-ESI.sup.- (m/z): [M-H].sup.- calcd for
C.sub.31H.sub.33N.sub.2O.sub.4: 497.2. Found: 497.2.
Example 37
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinolin-
-6-yl)acetic acid (37A) and
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)acetic acid (37B)
##STR00166##
[0923] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)ethyl pivalate: The solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (35 mg,
0.06 mmol), ethynylbenzene (8 .mu.L, 0.08 mmol), and triethylamine
(1 mL) in ethyl acetate (0.5 mL) was degassed with nitrogen.
Copper(I) iodide (1 mg) and bis(triphenylphosphine)palladium (II)
dichloride (7 mg) were added, and the mixture was stirred for 12
hours. The mixture was diluted with ethyl acetate, washed with
water and brine, and dried with sodium sulfate. Concentration and
purification by flash column chromatography (silica gel, ethyl
acetate/hexanes) gave
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)ethyl pivalate. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.35H.sub.37ClNO.sub.3: 554.2. Found: 554.3.
[0924] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)ethanol:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)ethanol (12 mg) was prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethanol of Example 29 except using
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)ethyl pivalate instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethyl pivalate. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.30H.sub.29ClNO.sub.2: 470.2. Found: 470.2.
[0925] Preparation
of(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quino-
lin-6-yl)acetic acid (37A):
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)acetic acid (4.9 mg) was prepared in a similar manner as
compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)acetic acid of Example 29 except using
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)ethanol instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethanol. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 7.95 (m, 1H),
7.90 (s, 1H), 7.7-7.6 (m, 6H), 7.50 (m, 3H), 7.37 (d, J=8.8 Hz,
1H), 5.23 (s, 1H), 2.72 (s, 3H), 0.99 (s, 9H); LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.30H.sub.27ClNO.sub.3: 484.2.
Found: 484.2. Preparation
of(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6--
yl)ethanol: The mixture of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)ethanol (6 mg) and rhodium on alumina (2 mg) in ethanol (1.5
mL) was stirred under 1 atm of hydrogen for 3 hours. Celite was
added, and the mixture was filtered and washed with ethyl acetate.
Concentration of the mother liquor under reduced pressure gave
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl-
)ethanol (6.5 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.30H.sub.33ClNO.sub.2: 474.2. Found: 474.3.
[0926] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl-
)acetic acid (37B):
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl-
)acetic acid (4.8 mg) was prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)acetic acid of Example 29 except using
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl-
)ethanol instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethanol. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.21 (d, J=8
Hz, 1H), 7.93 (s, 1H), 7.7-7.6 (m, 4H), 7.37 (d, J=8 Hz, 1H),
7.3-7.15 (m, 5H), 5.24 (s, 1H), 3.46 (d, J=7.6 Hz, 2H), 3.18 (d,
J=7.6 Hz, 2H), 2.76 (s, 3H), 0.96 (s, 9H); LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.30H.sub.31ClNO.sub.3: 488.2. Found:
488.2.
Example 38
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(cyclopropylethynyl)-7-methylqui-
nolin-6-yl)acetic acid (38)
##STR00167##
[0928]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(cyclopropylethynyl)-7-me-
thylquinolin-6-yl)acetic acid (38) (5.5 mg) was prepared in a
similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)acetic acid of Example 37 except using ethynylcyclopropane
instead of ethynylbenzene. .sup.1H-NMR 400 MHz (CD.sub.3OD) 8.0 (m,
1H), 7.84 (s, 1H), 7.64-7.55 (4H, m), 7.35 (d, J=7.6 Hz, 1H), 5.21
(s, 1H), 2.72 (s, 3H), 1.65 (m, 1H), 1.13-1.02 (m, 4H), 0.98 (s,
9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.27H.sub.27ClNO.sub.3: 448.2. Found: 448.2.
Example 39
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(2-cyclopropylethyl)-7-methylqui-
nolin-6-yl)acetic acid (39)
##STR00168##
[0930]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(2-cyclopropylethyl)-7-me-
thylquinolin-6-yl)acetic acid (39) (5.7 mg) was prepared in a
similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl-
)acetic acid of Example 37 except using ethynylcyclopropane instead
of ethynylbenzene. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.17
(d, J=8.4 Hz, 1H), 7.91 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.6-7.5
(m, 3H), 7.31 (m, 1H), 5.18 (s, 1H), 3.21 (m, 2H), 2.71 (s, 3H),
1.72 (m, 2H), 0.92 (s, 9H), 0.75 (m, 1H), 0.41 (m, 2H), 0.02 (m,
2H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.27H.sub.31ClNO.sub.3: 452.2. Found: 452.2.
Example 40
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(phenylethynyl)quinolin-6-yl)acetic acid: (40)
##STR00169##
[0932]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(phenylethynyl)quinolin-6-yl)acetic acid (40) (4.9
mg) was prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)acetic acid of Example 37 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsul-
fonyloxy)quinolin-6-yl)ethyl pivalate. .sup.1H-NMR 400 MHz
(CD.sub.3OD) .delta. 8.71 (d, J=5.2 Hz, 1H), 8.10 (s, 1H), 7.9-7.8
(m, 2H), 7.65 (m, 2H), 7.58 (m, 2H), 7.45 (m, 4H), 5.26 (s, 1H),
4.75 (m, 2H), 3.64 (m, 2H), 2.85 (s, 3H), 0.94 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.35H.sub.31N.sub.2O.sub.4: 543.2. Found: 543.1; LCMS-ESI.sup.-
(m/z): [M-H].sup.- calcd for C.sub.35H.sub.29N.sub.2O.sub.4: 541.2.
Found: 541.0.
Example 41
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-phenethylquinolin-6-yl)acetic acid: (41)
##STR00170##
[0934]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-phenethylquinolin-6-yl)acetic acid (41) (5.2 mg) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl-
)acetic acid of Example 37 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsul-
fonyloxy)quinolin-6-yl)ethyl pivalate. .sup.1H-NMR 400 MHz
(CD.sub.3OD) .delta. 8.51 (d, J=5.7 Hz, 1H), 7.96 (s, 1H), 7.80 (d,
J=8.8 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.45 (m, 2H), 7.2-7.05 (m,
6H), 5.15 (s, 1H), 4.56 (m, 2H), 3.35 (d, J=6.8 Hz, 2H), 3.22 (m,
2H), 3.07 (t, J=7.2 Hz, 2H), 2.80 (s, 3H), 0.82 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.35H.sub.35N.sub.2O.sub.4: 547.2. Found: 547.2; LCMS-ESI.sup.-
(m/z): [M-H].sup.- calcd for C.sub.35H.sub.33N.sub.2O.sub.4: 545.2.
Found: 545.1.
Example 42
(S)-2-tert-butoxy-2-((R)-2-(cyclopropylethynyl)-5-(2,3-dihydropyrano[4,3,2-
-de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (42)
##STR00171##
[0936]
(S)-2-tert-butoxy-2-((R)-2-(cyclopropylethynyl)-5-(2,3-dihydropyran-
o[4,3,2-de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (42)
(5.2 mg) was prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)acetic acid of Example 37 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
and ethynylcyclopropane instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate and ethynylbenzene. .sup.1H-NMR
400 MHz (CD.sub.3OD) .delta. 8.68 (d, J=5.6 Hz, 1H), 8.0 (s, 1H),
7.80 (d, J=7.6 Hz, 1H), 7.74 (d, J=5.6 Hz, 1H), 7.5 (d, J=8.4 Hz,
1H), 7.41 (d, J=7.6 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 5.23 (s, 1H),
4.70 (m, 2H), 3.62 (m, 2H), 2.83 (s, 3H), 1.60 (m, 1H), 1.05-0.88
(m, 4H), 0.93 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.32H.sub.31N.sub.2O.sub.4: 507.2. Found: 507.1; LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.32H.sub.29N.sub.2O.sub.4: 505.2.
Found: 505.1.
Example 43
(S)-2-tert-Butoxy-2-((R)-2-(2-cyclopropylethyl)-5-(2,3-dihydropyrano[4,3,2-
-de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (43)
##STR00172##
[0938]
(S)-2-tert-butoxy-2-((R)-2-(2-cyclopropylethyl)-5-(2,3-dihydropyran-
o[4,3,2-de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (43)
(5.9 mg) was prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl-
)acetic acid of Example 37 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
and ethynylcyclopropane instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate and ethynylbenzene. .sup.1H-NMR
400 MHz (CD.sub.3OD) .delta. 8.55 (m, 1H), 8.03 (s, 1H), 7.92 (d,
J=8.4 Hz, 1H), 7.62-7.45 (m, 3H), 7.23 (d, J=7.6 Hz, 1H), 5.19 (s,
1H), 4.78 (m, 2H), 3.43 (m, 2H), 3.20 (m, 2H), 2.84 (s, 3H), 1.65
(m, 2H), 0.84 (s, 9H), 0.7 (m, 1H), 0.4 (m, 2H), 0.02 (m, 2H);
LCMS-ESI.sup.+ (m/z): [M+11].sup.+ calcd for
C.sub.32H.sub.35N.sub.2O.sub.4: 511.2. Found: 511.2; LCMS-ESI.sup.-
[M-H].sup.- calcd for C.sub.32H.sub.33N.sub.2O.sub.4: 509.2. Found:
509.1.
Example 44
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(prop-1-ynyl)quinolin-6-yl)acetic acid (44)
##STR00173##
[0940]
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(prop-1-ynyl)quinolin-6-yl)acetic acid (44) (4.6 mg)
was prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)acetic acid of Example 37 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
and prop-1-yne instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate and ethynylbenzene. .sup.1H-NMR
400 MHz (CD.sub.3OD). .delta.8.67 (d, J=5.6 Hz, 1H), 8.02 (s, 1H),
7.85-7.75 (m, 2H), 7.5-7.4 (m, 1H), 7.42 (d, J=8 Hz, 1H), 7.35 (d,
J=8.8 Hz, 1H), 5.23 (s, 1H), 4.70 (m, 2H), 3.62 (m, 2H), 2.83 (s,
3H), 2.15 (s, 3H), 0.93 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calcd for C.sub.30H.sub.29N.sub.2O.sub.4: 481.2. Found: 481.4;
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.30H.sub.27N.sub.2O.sub.4: 479.2. Found: 479.1.
Example 45
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-et-
hynyl-7-methylquinolin-6-yl)acetic acid (45)
##STR00174##
[0942]
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-2-ethynyl-7-methylquinolin-6-yl)acetic acid (45) (5 mg) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinoli-
n-6-yl)acetic acid of Example 37 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
and ethynyltrimethylsilane instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate and ethynylbenzene. .sup.1H-NMR
400 MHz (CD.sub.3OD) .delta. 8.69 (d, J=5.6 Hz, 1H), 8.07 (s, 1H),
7.85-7.75 (m, 2H), 7.5-7.4 (m, 3H), 5.24 (s, 1H), 4.75 (m, 2H),
3.98 (s, 1H), 3.65 (m, 2H), 2.83 (s, 3H), 0.93 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.29H.sub.27N.sub.2O.sub.4: 467.2. Found: 467.1; LCMS-ESI.sup.-
(m/z): [M-H].sup.- calcd for C.sub.29H.sub.25N.sub.2O.sub.4: 465.2.
Found: 465.0.
Example 46
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-is-
opropyl-7-methylquinolin-6-yl)acetic acid (46)
##STR00175##
[0944] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)ethyl pivalate: To a solution of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
(compound of Example 36) (40 mg, 0.06 mmol) in THF/NMP (0.75 mL/75
.mu.L) was added iron (III) acetylacetonate (2 mg), followed by
isopropylmagnesium bromide (1.0 N, 0.14 mL, 0.14 mmol) slowly. The
mixture was stirred for 30 minutes, and was quenched with water.
Ethyl acetate was added, and the organic layer was separated,
washed with brine and dried with sodium sulfate. Concentration and
purification by flash column chromatography (hexanes/EtOAc) gave
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)ethyl pivalate (11 mg).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.35H.sub.43N.sub.2O.sub.4: 555.3. Found: 555.4.
[0945] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)ethanol:
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)ethanol (8 mg) was prepared in a
similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethanol of Example 29 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)ethyl pivalate instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethyl pivalate. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.30H.sub.35N.sub.2O.sub.3: 471.3. Found: 471.3.
[0946] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)acetic acid (46):
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)acetic acid (7 mg) was prepared in a
similar manner as compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)acetic acid of Example 29 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)ethanol instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethanol. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.60 (d, J=5.2
Hz, 1H), 8.11 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.7-7.6 (m, 2H),
7.51 (d, J=4.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 5.26 (s, 1H), 4.64
(m, 2H), 3.55-3.40 (m, 3H), 2.90 (s, 3H), 1.46 (m, 6H), 0.91 (s,
9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.30H.sub.33N.sub.2O.sub.4: 485.2. Found: 485.2; LCMS-ESI
(m/z): [M-H].sup.- calcd for C.sub.30H.sub.31N.sub.2O.sub.4: 483.2.
Found: 483.2.
Example 47
(S)-2-tert-butoxy-2-((R)-2-cyclobutyl-5-(2,3-dihydropyrano[4,3,2-de]quinol-
in-7-yl)-7-methylquinolin-6-yl)acetic acid (47)
##STR00176##
[0948]
(S)-2-tert-butoxy-2-((R)-2-cyclobutyl-5-(2,3-dihydropyrano[4,3,2-de-
] quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (47) (10 mg) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)acetic acid of Example 46 except
using cyclobutylmagnesium bromide instead of isopropylmagnesium
bromide. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.60 (m, 1H),
8.10 (m, 1H), 7.95 (m, 1H), 7.65 (m, 2H), 7.45 (m, 1H), 7.24 (m,
1H), 5.25 (s, 1H), 4.63 (m, 2H), 3.5 (m, 2H), 3.30 (m, 1H), 2.90
(s, 3H), 2.6-2.4 (m, 4H), 2.3 (m, 1H), 2.0 (m, 1H), 0.91 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.33N.sub.2O.sub.4: 497.2. Found: 497.2; LCMS-ESI
(m/z): [M-H].sup.- calcd for C.sub.31H.sub.31N.sub.2O.sub.4: 495.2.
Found: 495.2.
Example 48
(S)-2-((R)-2-(but-3-enyl)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethylquinolin-6-yl)-2-tert-butoxyacetic acid (48)
##STR00177##
[0950]
(S)-2-((R)-2-(but-3-enyl)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7--
yl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic acid (48) (12 mg))
was prepared in a similar manner as compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)acetic acid of Example 46 except
using but-3-enylmagnesium bromide instead of isopropylmagnesium
bromide. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.62 (m, 1H),
8.09 (s, 1H), 7.94 (m, 1H), 7.68 (m, 1H), 7.57 (m, 2H), 7.32 (m,
1H), 5.90 (m, 1H), 5.25 (s, 1H), 5.08 (m, 2H), 4.64 (m, 2H), 3.52
(m, 2H), 3.25 (m, 2H), 2.90 (s, 3H), 2.62 (m, 2H), 0.91 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.33N.sub.2O.sub.4: 497.2. Found: 497.2; LCMS-ESI
(m/z): [M-H].sup.- calcd for C.sub.31H.sub.31N.sub.2O.sub.4: 495.2.
Found: 495.1.
Example 49
(2S)-2-tert-Butoxy-2-((5R)-2-sec-butyl-5-(2,3-dihydropyrano[4,3,2-de]quino-
lin-7-yl)-7-methylquinolin-6-yl)acetic acid (49)
##STR00178##
[0952]
(2S)-2-tert-butoxy-2-((5R)-2-sec-butyl-5-(2,3-dihydropyrano[4,3,2-d-
e]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (49) (9.4 mg)
was prepared in a similar manner as compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)acetic acid of Example 46 except
using sec-butylmagnesium bromide instead of isopropylmagnesium
bromide. .sup.1H-NMR 400 MHz (CD.sub.3OD) 8.58 (d, J=4.4 Hz, 1H),
8.10 (s, 1H), 7.96 (m, 1H), 7.67-7.58 (m, 2H), 7.48 (m, 1H), 7.26
(d, J=8 Hz, 1H), 5.25 (s, 1H), 4.62 (m, 2H), 3.48 (m, 2H), 3.2 (m,
1H), 2.90 (s, 3H), 1.85 (m, 2H), 1.44 (m, 3H), 0.91 (m, 12H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.35N.sub.2O.sub.4: 499.2. Found: 499.2; LCMS-ESI
(m/z): [M-H].sup.- calcd for C.sub.31H.sub.33N.sub.2O.sub.4: 497.2.
Found: 497.2.
Example 50
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-is-
obutyl-7-methylquinolin-6-yl)acetic acid (50)
##STR00179##
[0954]
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-2-isobutyl-7-methylquinolin-6-yl)acetic acid (50) (10 mg) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)acetic acid of Example 46 except
using isobutylmagnesium bromide instead of isopropylmagnesium
bromide. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.65 (d, J=5.2
Hz, 1H), 8.12 (s, 1H), 8.03 (d, J=9.2 Hz, 1H), 7.72 (d, J=8 Hz,
1H), 7.63-7.58 (m, 2H), 7.33 (d, J=8 Hz, 1H), 5.26 (s, 1H), 4.65
(m, 2H), 3.55 (m, 2H), 3.05 (d, J=7.2 Hz, 2H), 2.92 (s, 3H), 2.2
(m, 1H), 1.02 (d, J=6.8 Hz, 6H), 0.92 (s, 9H); LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.31H.sub.35N.sub.2O.sub.4: 499.2.
Found: 499.2; LCMS-ESI.sup.- (m/z): [M-H].sup.- calcd for
C.sub.31H.sub.33N.sub.2O.sub.4: 497.2. Found: 497.2.
Example 51
(S)-2-tert-Butoxy-2-((R)-2-cyclopentyl-5-(2,3-dihydropyrano[4,3,2-de]quino-
lin-7-yl)-7-methylquinolin-6-yl)acetic acid (51)
##STR00180##
[0956]
(S)-2-tert-Butoxy-2-((R)-2-cyclopentyl-5-(2,3-dihydropyrano[4,3,2-d-
e]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (51) (8 mg) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)acetic acid in of Example 46 except
using cyclopentylmagnesium bromide instead of isopropylmagnesium
bromide. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.63 (m, 1H),
8.12 (s, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.65 (m, 2H), 7.54 (m, 1H),
7.32 (m, 1H), 5.26 (s, 1H), 4.65 (m, 2H), 3.52 (m, 3H), 2.91 (s,
3H), 2.30 (m, 2H), 2.0-1.8 (m, 6H), 0.91 (s, 9H); LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.32H.sub.35N.sub.2O.sub.4: 511.2.
Found: 511.1; LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.32H.sub.33N.sub.2O.sub.4: 509.2 Found: 509.1.
Example 52
(S)-2-tert-Butoxy-2-((R)-2-cyclohexyl-5-(2,3-dihydropyrano[4,3,2-de]quinol-
in-7-yl)-7-methylquinolin-6-yl)acetic acid (52)
##STR00181##
[0958]
(S)-2-tert-Butoxy-2-((R)-2-cyclohexyl-5-(2,3-dihydropyrano[4,3,2-de-
]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (52) (11 mg) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)acetic acid in of Example 46 except
using cyclohexylmagnesium bromide instead of isopropylmagnesium
bromide. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.62 (m, 1H),
8.13 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.65 (m, 2H), 7.54 (m, 1H),
7.30 (d, J=8 Hz, 1H), 5.26 (s, 1H), 4.65 (m, 2H), 3.50 (m, 2H),
3.15 (m, 1H), 2.91 (s, 3H), 2.1-1.35 (m, 10H), 0.91 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.33H.sub.37N.sub.2O.sub.4: 525.3. Found: 525.2; LCMS-ESI.sup.-
(m/z): [M-H].sup.- calcd for C.sub.33H.sub.35N.sub.2O.sub.4: 523.3.
Found: 523.2.
Example 53
(S)-2-((R)-2-Benzyl-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methylq-
uinolin-6-yl)-2-tert-butoxyacetic acid: (53)
##STR00182##
[0960]
(S)-2-((R)-2-Benzyl-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7--
methylquinolin-6-yl)-2-tert-butoxyacetic acid (53) (8 mg) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-7-methylquinolin-6-yl)acetic acid of Example 46 except
using benzylmagnesium bromide instead of isopropylmagnesium
bromide. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.61 (m, 1H),
8.13 (s, 1H), 7.82-7.70 (m, 2H), 7.60 (m, 1H), 7.4-7.2 (m, 7H),
5.24 (s, 1H), 4.65 (m, 2H), 4.45 (s, 2H), 3.55 (m, 2H), 2.89 (s,
3H), 0.91 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+11].sup.+ calcd for
C.sub.34H.sub.33N.sub.2O.sub.4: 533.3. Found: 533.2; LCMS-ESI.sup.-
(m/z): [M-H].sup.- calcd for C.sub.34H.sub.31N.sub.2O.sub.4: 531.3.
Found: 531.1.
Example 54
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(2-
,6-dimethylphenyl)-7-methylquinolin-6-yl)acetic acid (54)
##STR00183##
[0962] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)ethyl pivalate:
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)ethyl pivalate (7.5 mg)
was prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)ethyl pivalate of Example 8 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
and 2,6-dimethylphenylboronic acid instead of
(S)-2-(5-bromo-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethy-
l pivalate and 4-chlorophenylboronic acid. LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.40H.sub.45N.sub.2O.sub.4: 617.3. Found:
617.5.
[0963] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)ethanol:
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)ethanol (5.5 mg) was
prepared in a similar manner as compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol of Example 29 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)ethyl pivalate instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethyl pivalate. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.35H.sub.37N.sub.2O.sub.3: 533.3. Found: 533.4.
[0964] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)acetic acid (54):
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)acetic acid (3.5 mg) was
prepared in a similar manner as compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)acetic acid of Example 29 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)ethanol instead of
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.66 (m, 1H),
8.13 (m, 1H), 7.95 (m, 1H), 7.80 (m, 1H), 7.64 (m, 1H), 7.45 (m,
1H), 7.4-7.25 (m, 2H), 7.23 (m, 2H), 5.29 (s, 1H), 4.68 (m, 2H),
3.57 (m, 2H), 2.89 (s, 3H), 2.06 (s, 6H), 0.94 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.35H.sub.35N.sub.2O.sub.4: 547.3. Found: 547.2; LCMS-ESI.sup.-
(m/z): [M-H].sup.- calcd for C.sub.35H.sub.33N.sub.2O.sub.4: 545.3.
Found: 545.2.
Example 55
(S)-2-tert-Butoxy-2-((R)-2-(3-chlorophenyl)-5-(2,3-dihydropyrano[4,3,2-de]-
quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (55)
##STR00184##
[0966]
(S)-2-tert-Butoxy-2-((R)-2-(3-chlorophenyl)-5-(2,3-dihydropyrano[4,-
3,2-de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (55) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)acetic acid (3.5 mg) of
Example 54 except using 3-chlorophenylboronic acid instead of
2,6-dimethylphenylboronic acid. .sup.1H-NMR 400 MHz (CD.sub.3OD)
.delta. 8.71 (d, J=5.6 Hz, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 8.04
(m, 1H), 7.9-7.75 (m, 3H), 7.6-7.4 (m, 4H), 5.27 (s, 1H), 4.74 (m,
2H), 3.66 (m, 2H), 2.86 (s, 3H), 0.95 (s, 9H); LCMS-LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.33H.sub.30ClN.sub.2O.sub.4:
553.2. Found: 553.1; LCMS-ESI.sup.- (m/z): [M-H].sup.- calcd for
C.sub.33H.sub.28ClN.sub.2O.sub.4: 551.2. Found: 551.1.
Example 56
(S)-2-tert-Butoxy-2-((R)-2-(4-chlorophenyl)-5-(2,3-dihydropyrano[4,3,2-de]-
quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (56)
##STR00185##
[0968]
(S)-2-tert-Butoxy-2-((R)-2-(4-chlorophenyl)-5-(2,3-dihydropyrano[4,-
3,2-de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (56) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)acetic acid (3.5 mg) of
Example 54 except using 4-chlorophenylboronic acid instead of
2,6-dimethylphenylboronic acid. .sup.1H-NMR 400 MHz (CD.sub.3OD)
.delta. 8.70 (d, J=5.2 Hz, 1H), 8.22 (s, 1H), 8.13 (d, J=8.4 HZ,
2H), 7.9-7.75 (m, 3H), 7.6-7.5 (m, 2H), 7.46 (d, J=8 Hz, 1H), 7.35
(d, J=8.4 Hz, 1H), 5.27 (s, 1H), 4.75 (m, 2H), 3.64 (m, 2H), 2.86
(s, 3H), 0.95 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.33H.sub.30ClN.sub.2O.sub.4: 553.2. Found: 553.1;
LCMS-ESI.sup.- (m/z): [M-H].sup.- calcd for
C.sub.33H.sub.28ClN.sub.2O.sub.4: 551.2. Found: 551.1.
Example 57
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-phenylquinolin-6-yl)acetic acid (57)
##STR00186##
[0970]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-phenylquinolin-6-yl)acetic acid (57) was prepared in
a similar manner as compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)acetic acid (3.5 mg) of
Example 54 except using phenylboronic acid instead of
2,6-dimethylphenylboronic acid. .sup.1H-NMR 400 MHz (CD.sub.3OD)
.delta. 8.71 (m, 1H), 8.24 (m, 1H), 8.12 (m, 2H), 7.85 (m, 2H),
7.75 (m, 2H), 7.60 (m, 3H), 7.43 (d, J=8 Hz, 1H), 5.28 (s, 1H),
4.69 (m, 2H), 3.63 (m, 2H), 2.88 (s, 3H), 0.95 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.33H.sub.31N.sub.2O.sub.4: 519.2. Found: 519.1.
Example 58
(S)-2-tert-Butoxy-2-((R)-2-cyclopropyl-5-(2,3-dihydropyrano[4,3,2-de]quino-
lin-7-yl)-7-methylquinolin-6-yl)acetic acid (58)
##STR00187##
[0972]
(S)-2-tert-Butoxy-2-((R)-2-cyclopropyl-5-(2,3-dihydropyrano[4,3,2-d-
e]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (58) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
2,6-dimethylphenyl)-7-methylquinolin-6-yl)acetic acid (3.5 mg) of
Example 54 except using cyclopropylboronic acid instead of
2,6-dimethylphenylboronic acid. .sup.1H-NMR 400 MHz (CD.sub.3OD)
.delta. 8.65 (d, J=5.2 Hz, 1H), 8.07 (s, 1H), 7.86 (d, J=8.8 Hz,
1H), 7.69 (d, J=8 Hz, 1H), 7.56 (d, J=4.8 Hz, 1H), 7.31 (d, J=8.4
Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 5.24 (s, 1H), 4.65 (m, 2H), 3.51
(m, 2H), 2.90 (s, 3H), 2.50 (m, 1H), 1.54 (m, 2H), 1.30 (m, 2H),
0.92 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.30H.sub.31N.sub.2O.sub.4: 483.2. Found: 483.2; LCMS-ESI
(m/z): [M-H].sup.- calcd for C.sub.30H.sub.29N.sub.2O.sub.4: 481.2.
Found: 481.2.
Example 59
(S)-2-(1,5-Bis(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2--
tert-butoxyacetic acid: (59)
##STR00188## ##STR00189##
[0974] Preparation of
(S)-2-(1,5-bis(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-
-tert-butoxyethyl pivalate: To the solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)ethyl pivalate (8J) (23 mg, 0.05 mmol) and
4-chlorophenylboronic acid (16 mg, 0.10 mmol) in dichloromethane (2
mL) was added copper (II) acetate (9 mg), followed by molecular
sieve 4 .ANG. and pyridine (82 .mu.L). The mixture was stirred for
5 days, and filtered and washed with ethyl acetate. Concentration
and purification by flash column chromatography (hexanes/EtOAc)
gave
(S)-2-(1,5-bis(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-
-tert-butoxyethyl pivalate (25 mg). LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.33H.sub.36Cl.sub.2NO.sub.4: 580.2.
Found: 580.0.
[0975] Preparation of
((S)-6-(1-tert-butoxy-2-hydroxyethyl)-1,5-bis(4-chlorophenyl)-7-methylqui-
nolin-2(1H)-one:
(S)-6-(1-tert-butoxy-2-hydroxyethyl)-1,5-bis(4-chlorophenyl)-7-methylquin-
olin-2(1H)-one was prepared in a similar manner as compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol of Example 29 except using
(S)-2-(1,5-bis(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-
-tert-butoxyethyl pivalate instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethyl pivalate. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.28H.sub.28Cl.sub.2NO.sub.3: 496.1. Found: 496.3.
[0976] Preparation of
((S)-2-(1,5-bis(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)--
2-tert-butoxyacetic acid (59):
(S)-2-(1,5-bis(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-
-tert-butoxyacetic acid was prepared in a similar manner as
compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)acetic acid of Example 29 except using
(S)-6-(1-tert-butoxy-2-hydroxyethyl)-1,5-bis(4-chlorophenyl)-7-methylquin-
olin-2(1H)-one instead of
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol. .sup.1H-NMR 400 MHz (CD.sub.3OD) 7.51 (m, 3H), 7.46 (m,
2H), 7.25 (d, J=9.6 Hz, 1H), 7.2-7.15 (m, 3H), 6.52 (d, J=9.6 Hz,
1H), 6.42 (s, 1H), 5.05 (s, 1H), 2.28 (s, 3H), 0.93 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.28H.sub.26Cl.sub.2NO.sub.4: 510.1. Found: 510.1.
Example 60
(S)-2-tert-Butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-is-
opropyl-8-methylimidazo[1,2-a]quinolin-7-yl)acetic acid: (60)
##STR00190## ##STR00191##
[0978] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
(S)-1,1-dimethoxy-3-methylbutan-2-ylamino)-7-methylquinolin-6-yl)ethyl
pivalate: The mixture of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
(compound of Example 36) (30 mg) and
(S)-1,1-dimethoxy-3-methylbutan-2-amine (70 mg) in 1,4-dioxane (1
mL) was heated at 160.degree. C. for 10 hours. The solution was
diluted with ethyl acetate, and was washed with 1.0 N sodium
hydroxide solution and brine, and dried with sodium sulfate.
Concentration and purification by flash column chromatography
(hexanes/EtOAc) gave
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
(S)-1,1-dimethoxy-3-methylbutan-2-ylamino)-7-methylquinolin-6-yl)ethyl
pivalate (22 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.39H.sub.52N.sub.3O.sub.6: 658.4. Found: 658.3.
[0979] Preparation of
(S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-8-methylimidazo[1,2-a]quinolin-7-yl)ethyl pivalate: The
mixture of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)--
2-((S)-1,1-dimethoxy-3-methylbutan-2-ylamino)-7-methylquinolin-6-yl)ethyl
pivalate (22 mg) and acetic acid (0.1 mL) in xylene (2 mL) was
heated at 180.degree. C. for 90 minutes. The solution was diluted
with ethyl acetate, and was washed with 1.0 N sodium hydroxide
solution and brine, and dried with sodium sulfate. Concentration
and purification by flash column chromatography (hexanes/EtOAc)
gave
(S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-8-methylimidazo[1,2-a]quinolin-7-yl)ethyl pivalate (8.7
mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.37H.sub.44N.sub.3O.sub.4: 594.3; Found: 594.4.
[0980] Preparation of
(S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-8-methylimidazo[1,2-a]quinolin-7-yl)ethanol:
(S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-8-methylimidazo[1,2-a]quinolin-7-yl)ethanol was prepared
in a similar manner as compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol of Example 29 except using
(S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-8-methylimidazo[1,2-a]quinolin-7-yl)ethyl pivalate instead
of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethyl pivalate. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.32H.sub.36N.sub.3O.sub.3: 510.3. Found: 510.3.
[0981] Preparation of
(S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-8-methylimidazo[1,2-a]quinolin-7-yl)acetic acid (60):
(S)-2-tert-Butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-8-methylimidazo[1,2-a]quinolin-7-yl)acetic acid was
prepared in a similar manner as compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)acetic acid of Example 29 except using
(S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-8-methylimidazo[1,2-a]quinolin-7-yl)ethanol instead of
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.8 (s, 1H),
8.65 (d, J=5.2 Hz, 1H), 8.58 (s, 1H), 7.7 (m, 1H), 7.6 (m, 1H),
7.4-7.2 (m, 3H), 5.23 (s, 1H), 4.65 (m, 2H), 3.55 (m, 2H), 3.3 (m,
1H), 2.93 (s, 3H), 1.50 (d, J=6.8 Hz, 6H), 0.93 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.32H.sub.34N.sub.3O.sub.4: 524.3. Found: 524.2; LCMS-ESI.sup.-
(m/z): [M-H].sup.- calcd for C.sub.32H.sub.32N.sub.3O.sub.4: 522.3.
Found: 522.1.
Example 61
(S)-2-tert-Butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-8-me-
thyl-2-phenylimidazo[1,2-a]quinolin-7-yl)acetic acid (61)
##STR00192##
[0983]
(S)-2-tert-Butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-8-methyl-2-phenylimidazo[1,2-a]quinolin-7-yl)acetic acid (61)
(2.9 mg) was prepared in a similar manner as compound
(S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-8-methylimidazo[1,2-a]quinolin-7-yl)acetic acid of Example
60 except using 2,2-dimethoxy-1-phenylethanamine instead of
(S)-1,1-dimethoxy-3-methylbutan-2-amine. .sup.1H-NMR 400 MHz
(CD.sub.3OD) .delta. 9.34 (s, 1H), 8.67 (m, 1H), 8.60 (m, 1H), 7.98
(m, 2H), 7.7 (m, 1H), 7.6-7.4 (m, 5H), 7.3 (m, 2H), 5.25 (s, 1H),
4.66 (m, 2H), 3.54 (m, 2H), 2.95 (s, 3H), 0.95 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.35H.sub.32N.sub.3O.sub.4: 558.2. Found: 558.2; Lcms-ESI.sup.-
(m/z): [m-H].sup.- calcd for C.sub.35H.sub.30N.sub.3O.sub.4: 556.2.
Found: 556.1.
Example 62
(S)-2-tert-Butoxy-2-(6-(4-chlorophenyl)-8-methylimidazo[1,2-a]quinolin-7-y-
l)acetic acid (62)
##STR00193##
[0985]
(S)-2-tert-Butoxy-2-(6-(4-chlorophenyl)-8-methylimidazo[1,2-a]quino-
lin-7-yl)acetic acid (62) was prepared in a similar manner as
compound
(S)-2-tert-butoxy-2-((R)-6-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-i-
sopropyl-8-methylimidazo[1,2-a]quinolin-7-yl)acetic acid of Example
60 except using
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate and 2,2-dimethoxyethanamine
instead of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
and (S)-1,1-dimethoxy-3-methylbutan-2-amine. .sup.1H-NMR 400 MHz
(CD.sub.3OD) .delta. 8.92 (m, 1H), 8.45 (m, 1H), 8.10 (m, 1H),
7.7-7.6 (m, 5H), 7.38 (m, 1H), 5.21 (s, 1H), 2.80 (s, 3H), 0.99 (s,
9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.24H.sub.24ClN.sub.2O.sub.3: 423. Found: 423.2; LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.24H.sub.22ClN.sub.2O.sub.3:
421.1. Found: 421.0.
Example 63
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]qui-
nolin-7-yl)acetic acid (63)
##STR00194## ##STR00195##
[0987] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-y-
l)ethyl pivalate: The mixture of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (10 mg)
and hydrazine in THF (1.0 N, 1 mL, 1 mmol) was heated at 80.degree.
C. for 12 hours. Concentration under reduced pressure gave
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-y-
l)ethyl pivalate, which was used for next step without
purification. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.27H.sub.35ClN.sub.3O.sub.3: 484.2. Found: 484.3.
[0988] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-y-
l)ethanol:
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylqu-
inolin-6-yl)ethanol was prepared in a similar manner as compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol of Example 29 except using
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-y-
l)ethyl pivalate instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethyl pivalate. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.22H.sub.27ClN.sub.3O.sub.2: 400.2. Found: 400.2.
[0989] Preparation of
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]qu-
inolin-7-yl)ethanol: The mixture of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-y-
l)ethanol and triethyl orthoformate (0.5 mL) in butanol (5 mL) was
heated at 100.degree. C. for 12 hours. The solution was diluted
with ethyl acetate, and was washed with 1.0 N sodium hydroxide
solution and brine, and dried with sodium sulfate. Concentration
and purification by flash column chromatography (hexanes/EtOAc)
gave
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]qu-
inolin-7-yl)ethanol (3.3 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calcd for C.sub.23H.sub.25ClN.sub.3O.sub.2: 410.2. Found:
410.2.
[0990] Preparation of
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]qu-
inolin-7-yl)acetic acid (63):
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]qu-
inolin-7-yl)acetic acid was prepared in a similar manner as
compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)acetic acid of Example 29 except using
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]qu-
inolin-7-yl)ethanol instead of
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 9.95 (s, 1H),
8.34 (s, 1H), 7.6 (m, 3H), 7.54 (m, 1H), 7.35 (m, 2H), 5.17 (s,
1H), 2.75 (s, 3H), 0.99 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calcd for C.sub.23H.sub.23ClN.sub.3O.sub.3: 424.1. Found: 424.2;
LCMS-EST (m/z): [M-H].sup.- calcd for
C.sub.23H.sub.21ClN.sub.3O.sub.3: 422.1Found: 421.9.
Example 64
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin-7-
-yl)acetic acid (64)
Scheme 9
##STR00196##
[0992] Preparation of
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin--
7-yl)ethyl pivalate: The mixture of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26)(30 mg)
and sodium azide (32 mg) in DMF (1 mL) was heated at 90.degree. C.
for 4 hours. The mixture was diluted with ethyl acetate, and washed
with water and brine, and dried with sodium sulfate. Concentration
and purification by flash column chromatography (hexanes/EtOAc)
gave
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin--
7-yl)ethyl pivalate (5.9 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calcd for C.sub.27H.sub.32ClN.sub.4O.sub.3: 495.2. Found:
495.2.
[0993] Preparation of
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin--
7-yl)ethanol:
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin--
7-yl)ethanol (5 mg) was prepared in a similar manner as compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol of Example 29 except using
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin--
7-yl)ethyl pivalate instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-y-
l)ethyl pivalate. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.22H.sub.24ClN.sub.4O.sub.2: 411.2. Found: 411.1.
[0994] Preparation of
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin--
7-yl)acetic acid (64):
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin--
7-yl)acetic acid (4.9 mg) was prepared in a similar manner as
compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)acetic acid of Example 29 except using
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin--
7-yl)ethanol instead of
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol. .sup.1H-NMR 400 MHz (CD.sub.3OD) 8.61 (s, 1H), 7.75 (d,
J=9.6 Hz, 1H), 7.67-7.55 (m, 4H), 7.39 (d, J=9.2 HZ, 1H), 5.2 (s,
1H), 2.79 (s, 3H), 1.00 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calcd for C.sub.22H.sub.22ClN.sub.4O.sub.3: 425.1. Found:
425.1.
Example 65
(S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-buto-
xyacetic acid (65A) and
(S)-2-(1-benzyl-5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-y-
l)-2-tert-butoxyacetic acid (65B)
##STR00197##
[0996] Preparation of
(S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-but-
oxyethanol and
(S)-1-benzyl-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methyl-
quinolin-2(1H)-one: To the solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)ethyl pivalate (8J) (16 mg, 0.03 mmol) in DMF (1 mL) was
added sodium hydride (7 mg, 60% oil, 0.17 mmol). The mixture was
stirred for 30 minutes, and benzyl bromide (64, 0.05 mmol) was
added. The mixture was stirred another 90 minutes, and was quenched
with water, and left for 12 hours. The mixture was extracted with
ethyl acetate, and the organic layer was washed with water and
brine, and dried over sodium sulfate. Concentration and
purification by flash column chromatography (hexanes/EtOAc) gave
(S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-but-
oxyethanol (3.1 mg). LCMS-ESI.sup.+ (m/z): [M-FH].sup.+ calcd for
C.sub.29H.sub.30ClNO.sub.3: 476.2. Found: 476.1.
(S)-1-Benzyl-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methyl-
quinolin-2(1H)-one was also isolated 6.1 mg LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.29H.sub.31ClNO.sub.3: 476.2. Found: 476.2.
[0997] Preparation of
(S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-but-
oxyacetic acid:
(S)-2-(2-(Benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-but-
oxyacetic acid (65A) (3.3 mg) was prepared in a similar manner as
compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)acetic acid of Example 29 except using
(S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-but-
oxyethanol instead of
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 7.82 (d, J=9.6
Hz, 1H), 7.71 (s, 1H), 7.80 (m, 3H), 7.51 (m, 2H), 7.41-7.10 (m,
4H), 7.12 (d, J=9.6 Hz, 1H), 5.58 (s, 2H), 5.18 (s, 1H), 2.66 (s,
3H), 0.97 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.29H.sub.29ClNO.sub.4: 490.2. Found: 490.2.
[0998] Preparation of
(S)-2-(1-benzyl-5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-y-
l)-2-tert-butoxyacetic acid:
(S)-2-(1-Benzyl-5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-y-
l)-2-tert-butoxyacetic acid (65B) (5.4 mg) was prepared in a
similar manner as compound
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)acetic acid of Example 29 except using
(S)-1-benzyl-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methyl-
quinolin-2(1H)-one instead of
((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6--
yl)ethanol. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 7.6-7.5 (m,
3H), 7.4-7.2 (m, 8H), 6.59 (d, J=9.6 Hz, 1H), 5.64 (s, 2H), 5.02
(s, 1H), 2.47 (s, 3H), 0.94 (s, 9H); LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.29H.sub.29ClNO.sub.4: 490.2. Found:
490.2; LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.29H.sub.27ClNO.sub.4: 488.2. Found: 488.0.
Example 66
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-methoxy-7-methylquinolin-6-yl)ac-
etic acid: (66)
##STR00198##
[1000]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-methoxy-7-methylquinolin--
6-yl)acetic acid (66) (2.3 mg) was prepared in a similar manner as
compound
(S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-
-tert-butoxyacetic acid of Example 65 except using iodomethane
instead of benzyl bromide. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta.
7.68 (s, 1H), 7.6-7.5 (m, 4H), 7.30 (d, J=8 Hz, 1H), 6.87 (d, J=9.6
Hz, 1H), 5.16 (s, 1H), 4.08 (s, 3H), 2.62 (s, 3H), 0.97 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.23H.sub.25ClNO.sub.4: 414.1. Found: 414.2; LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.23H.sub.23ClNO.sub.4: 412.1.
Found: 412.0.
Example 67
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-1,7-dimethyl-2-oxo-1,2-dihydroquin-
olin-6-yl)acetic acid (67)
##STR00199##
[1002]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-1,7-dimethyl-2-oxo-1,2-dihy-
droquinolin-6-yl)acetic acid (67) (2.0 mg) was prepared in a
similar manner as compound
(S)-2-(1-benzyl-5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-y-
l)-2-tert-butoxyacetic acid of Example 65 except using iodomethane
instead of benzyl bromide. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta.
7.6-7.5 (m, 4H), 7.3-7.26 (m, 2H), 6.49 (d, J=10 Hz, 1H), 5.06 (s,
1H), 3.78 (s, 3H), 2.64 (s, 3H), 0.97 (s, 9H); LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.23H.sub.25ClNO.sub.4: 414.1.
Found: 414.2; LCMS-ESI.sup.- (m/z): [M-H].sup.- calcd for
C.sub.23H.sub.23ClNO.sub.4: 412.1. Found: 412.0.
Example 68
(S)-2-((R)-1-benzyl-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl--
2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyacetic acid (68)
##STR00200##
[1004] (S)-2-((R)-1-Benzyl-5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyacet-
ic acid (68) (1.0 mg) was prepared in a similar manner as compound
(S)-2-(1-benzyl-5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-y-
l)-2-tert-butoxyacetic acid of Example 65 except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl
pivalate instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinoli-
n-6-yl)ethyl pivalate. .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta.
8.68 (m, 1H), 7.9 (m, 1H), 7.75 (m, 1H), 7.6 (m, 3H), 7.43 (m, 4H),
7.06 (d, J=9.2 Hz, 1H), 6.37 (d, J=9.6 Hz, 1H), 5.49 (s, 2H), 5.07
(s, 1H), 4.83 (m, 2H), 3.50 (m, 2H), 2.72 (s, 3H), 0.90 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.34H.sub.33N.sub.2O.sub.5: 549.2. Found: 549.1; LCMS-ESI.sup.-
(m/z): [M-H].sup.- calcd for C.sub.34H.sub.31N.sub.2O.sub.5:
547.22. Found: 547.1.
Example 69
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(thiophen-2-yl)quinolin-6-yl)acetic acid (69)
##STR00201##
[1006] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(thiophen-2-yl)quinolin-6-yl)ethyl pivalate: To a solution
of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
(compound of Example 36) (50 mg, 0.08 mmol) in 1,2-dimethoxyethane
was added thiophen-2-ylboronic acid (15 mg, 0.114 mmol), 2 M
potassium carbonate (0.15 mL, 0.30 mmol) and Pd(PPh.sub.3).sub.4 (9
mg, 0.008 mmol) and the resulting solution was degassed 5 minutes
with argon. The mixture was then heated for 20 minutes at
110.degree. C. in a microwave reactor. The crude reaction was
absorbed onto silica gel and purified by flash column
chromatography (silica gel, ethyl acetate/hexanes) to give a brown
film (23.2 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.36H.sub.39N.sub.2O.sub.4S: 595.26. found: 595.48.
[1007] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(thiophen-2-yl)quinolin-6-yl)ethanol: To a solution of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(thiophen-2-yl)quinolin-6-yl)ethyl pivalate (23 mg, 0.039
mmol) in tetrahydrofuran and methanol (5:1, 3 mL) was added 1 M
sodium hydroxide (2 mL) and the reaction was heated to 45.degree.
C. overnight. An additional 2 mL of 1 M sodium hydroxide was added
and the reaction was stirred at room temperature over the weekend.
The reaction was diluted with water and extracted with ethyl
acetate. The organic layer was washed with brine and then dried
over sodium sulfate and concentrated to give a yellow film (14 mg).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.31N.sub.2O.sub.3S: 511.20. found: 511.40.
[1008] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(thiophen-2-yl)quinolin-6-yl)acetic acid (69): To a
solution of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(thiophen-2-yl)quinolin-6-yl)ethanol in wet acetonitrile at
0.degree. C. was added 0.4 M CrO.sub.3/H.sub.5IO.sub.6 (0.206 mL,
0.082 mmol). The solution was stirred at 0.degree. C. for 3 hours,
and an additional 0.082 mmol of 0.4 M CrO.sub.3/H.sub.5IO.sub.6 was
added. The reaction was quenched with 1 M
NaH.sub.2PO.sub.42H.sub.2O and extracted with ethyl acetate. The
organic layer was concentrated and purified by reverse phase HPLC
(Gemini, 10-55% ACN/H.sub.2O+0.1% TFA). Product lyophilized to give
a yellow powder (4 mg). .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.:
8.62 (d, J=5.2 Hz, 1H), 7.96 (s, 1H), 7.76 (d, J=3.2 Hz, 1H), 7.70
(d, J=7.6 Hz, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.58 (d, J=4.4 Hz, 1H),
7.51 (d, J=5.2 Hz, 1H), 7.29 (d, J=8 Hz, 2H), 7.17 (t, J=3.2 Hz,
1H), 5.19 (s, 1H), 4.62 (m, 2H), 3.48 (t, J=6.0, 2H), 2.72 (s, 3H),
0.92 (s, 9H).
[1009] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.29N.sub.2O.sub.4S: 425.18. found: 425.25.
Example 70
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl)quinol-
in-6-yl)acetic acid (70)
##STR00202##
[1011]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl-
)quinolin-6-yl)acetic acid (70) was prepared using the procedure to
prepare
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-
-yl)-7-methyl-2-(thiophen-2-yl)quinolin-6-yl)acetic acid of Example
69 except that
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate was used instead of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
and 1H-pyrazol-5-ylboronic acid was used instead of
thiophen-2-ylboronic acid. Additionally, in the second step the
crude extract was co-evaporated two times with acetonitrile and in
the final step the CrO.sub.3/H.sub.5IO.sub.6 was added in one
portion and stirred 2 hours. .sup.1H-NMR: 400 MHz, (CD.sub.3CN)
.delta.: 8.06 (s, 1H), 7.98 (AB.sub.q, J=22.4, 8.8 Hz, 2H), 7.78
(s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.58 (m, 2H), 7.37 (d, J=8.4 Hz,
1H), 7.33 (d, J=7.2 Hz, 1H), 7.20 (s, 1H), 5.23 (s, 1H), 2.64 (s,
3H), 097 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.25ClN.sub.3O.sub.3: 450.15. found: 450.62.
Example 71
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(1H-pyrazol-5-yl)quinolin-6-yl)acetic acid (71)
##STR00203##
[1013]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(1H-pyrazol-5-yl)quinolin-6-yl)acetic acid (71) was
prepared using the procedure to prepare
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(thiophen-2-yl)quinolin-6-yl)acetic acid of Example 69
except that 1H-pyrazol-5-ylboronic acid was used instead of
thiophen-2-ylboronic acid, in the second step the crude extract was
co-evaporated two times with acetonitrile and in the final step the
CrO.sub.3/H.sub.5IO.sub.6 was added in one portion and stirred for
2 hours. .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 8.64 (d, J=4.8
Hz, 1H), 8.07 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.69 (d, J=2.0 Hz,
1H), 7.66 (d, J=8.4 Hz, 1H), 7.49 (m, 2H), 7.26 (d, J=8.0 Hz, 1H),
7.09 (d, J=2.0 Hz, 1H), 5.19 (s, 1H), 4.61 (m, 2H), 3.46 (t, J=6.0
Hz, 2H), 2.74 (s, 3H), 0.91 (s, 9H). LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.30H.sub.29N.sub.4O.sub.4: 509.21.
found: 509.26.
Example 72
(S)-2-tert-butoxy-2-4R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-met-
hyl-2-(pyrimidin-5-yl)quinolin-6-yl)acetic acid (72)
##STR00204##
[1015]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(pyrimidin-5-yl)quinolin-6-yl)acetic acid (72) was
prepared using the procedure to prepare
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(1H-pyrazol-5-yl)quinolin-6-yl)acetic acid of Example 71
except that pyrimidin-5-ylboronic acid was used instead of
1H-pyrazol-5-ylboronic acid and the final reaction was stirred 1
hour. .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 9.43 (s, 2H),
9.19 (s, 1H), 8.63 (d, J=4.8 Hz, 1H), 8.08 (s, 1H), 7.76 (d, J=8.8
Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.50 (d, J=5.2 Hz, 1H), 7.44 (d,
J=8.4 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 5.22 (s, 1H), 4.62 (m, 2H),
3.48 (t, J=5.6 Hz, 2H), 2.75 (s, 3H), 094 (s, LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.31H.sub.29N.sub.4O.sub.4: 521.21.
found: 521.18.
Example 73
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-4-yl)quinolin--
6-yl)acetic acid (73)
##STR00205##
[1017]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-4-yl)qu-
inolin-6-yl)acetic acid (73) was prepared following the procedure
used for
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl)quino-
lin-6-yl)acetic acid of Example 70 except that pyridin-4-ylboronic
acid was used instead of 1H-pyrazol-5-ylboronic acid and in the
final step the reaction was stirred for 3 hours.
[1018] .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 8.84 (s, 2H),
8.46 (d, J=5.6 Hz, 2H), 8.03 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.87
(d, J=8.8 Hz, 1H), 7.60 (m, 3H), 7.37 (d, J=8 Hz, 1H), 5.27 (s,
1H), 2.66 (s, 3H), 0.99 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calcd for C.sub.27H.sub.25ClN.sub.2O.sub.3: 461.16. found:
461.64.
Example 74
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-3-yl)quinolin--
6-yl)acetic acid (74)
##STR00206##
[1020]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-3-yl)qu-
inolin-6-yl)acetic acid (74) was prepared following the procedure
for
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-4-yl)quinolin-
-6-yl)acetic acid of Example 73 except that pyridin-3-ylboronic
acid was used instead of pyridin-4-ylboronic acid. .sup.1H-NMR: 400
MHz, (CD.sub.3CN) .delta.: 9.49 (s, 1H), 8.94 (d, J=8.4 Hz, 1H),
8.79 (s, 1H), 7.91 (m, 2H), 7.80 (Abq, J=26.2, 8.8 Hz, 2H), 7.58
(m, 3H), 7.34 (m, 1H), 5.25 (s, 1H), 2.61 (s, 3H), 0.97 (s, 9H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.27H.sub.26ClN.sub.2O.sub.3: 461.16. found: 461.00.
Example 75
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(pyridin-4-yl)quinolin-6-yl)acetic acid (75)
##STR00207##
[1022]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(pyridin-4-yl)quinolin-6-yl)acetic acid (75) was
prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-7-methyl-2-(1H-pyrazol-5-yl)quinolin-6-yl)acetic
acid of Example 71 except that pyridin-4-ylboronic acid was used
instead of 1H-pyrazol-5-ylboronic acid and the final reaction was
stirred for 1 hour. .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.:
8.82 (br s, 2H), 8.63 (d, J=4.4 Hz, 1H), 8.48 (d, J=5.2 Hz, 2H),
8.10 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 7.48
(d, J=8.8 Hz, 1H), 7.45 (d, J=5.2 Hz, 1H), 7.25 (d, J=8 Hz, 1H),
5.24 (s, 1H), 4.60 (m, 2H), 3.44 (t, J=6 Hz, 2H), 2.75 (s, 3H),
0.92 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.32H.sub.30N.sub.3O.sub.4: 520.22. found: 520.22.
Example 76
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(thiazol-4-yl)quinolin--
6-yl)acetic acid (76)
##STR00208##
[1024]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(thiazol-4-yl)qu-
inolin-6-yl)acetic acid (76) was prepared following the procedure
for
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl)quino-
lin-6-yl)acetic acid of Example 70 except that thiazol-4-ylboronic
acid was used instead of 1H-pyrazol-5-ylboronic acid and the in the
final step the reaction was stirred for 1.5 hours. .sup.1H-NMR: 400
MHz, (CD.sub.3CN) .delta.: 9.07 (d, J=2.0 Hz, 1H), 8.58 (d, J=2.0
Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 8.02 (s, 1H), 7.93 (d, J=9.2 Hz,
1H), 7.59 (m, 3H), 7.35 (d, J=7.6 Hz, 1H), 5.25 (s, 1H), 2.64 (s,
3H), 0.98 (s, 9H).
[1025] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.24ClN.sub.2O.sub.3S: 467.11. found: 467.49.
Example 77
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-4-yl)quinol-
in-6-yl)acetic acid (77)
##STR00209##
[1027]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-4-yl-
)quinolin-6-yl)acetic acid (77) was prepared following the
procedure for
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl)quino-
lin-6-yl)acetic acid of Example 70 except that
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was
used instead of 1H-pyrazol-5-ylboronic acid and the in the final
step the reaction was stirred for 1 hour. .sup.1H-NMR: 400 MHz,
(CD.sub.3CN) .delta.: 8.45 (s, 2H), 8.08 (s, 1H), 7.89 (d, J=8.8
Hz, 1H), 7.73 9 (d, J=8.8 Hz, 1H), 7.59 (m, 3H), 7.34 (d, J=7.2 Hz,
1H), 5.22 (s, 1H), 2.63 (s, 3H), 0.97 (s, 9H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.25H.sub.25ClN.sub.3O.sub.3:
450.15. found: 450.53.
Example 78
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(1H-pyrazol-4-yl)quinolin-6-yl)acetic acid (78)
##STR00210##
[1029]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(1H-pyrazol-4-yl)quinolin-6-yl)acetic acid (78) was
prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(pyrimidin-5-yl)quinolin-6-yl)acetic acid of Example 71
except that
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was
used instead of 1H-pyrazol-5-ylboronic acid. .sup.1H-NMR: 400 MHz,
(CD.sub.3CN) .delta.: 8.64 (d, J=5.2 Hz, 1H), 8.50 (br s, 2H), 8.23
(s, 1H), 7.61 (m, 3H), 7.45 (d, J=5.2 Hz, 1H), 7.24 (d, J=8.0 Hz,
1H), 5.20 (s, 1H), 4.60 (m, 2H), 3.44 (t, J=6.0 Hz, 2H), 2.74 (s,
3H), 0.89 (s, 9H).
[1030] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.30H.sub.29N.sub.4O.sub.4: 509.21. found: 509.07.
Example 79
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-2-yl)quinolin--
6-yl)acetic acid (79)
##STR00211##
[1032] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-2-yl)quinolin-
-6-yl)ethyl pivalate: To a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26; 50 mg,
0.08 mmol) in 1,2 dimethoxyethane (1 mL) was added
2-(tributylstannyl)pyridine (0.040 mL, 0.125 mmol) and
Pd(PPh.sub.3).sub.4 and the reaction mixture was degassed with
argon for 5 minutes. The reaction was heated to 110.degree. C. in a
microwave reactor for 20 minutes. The crude reaction mixture was
absorbed onto silica gel and purified by flash column
chromatography (silica gel, ethyl acetate/hexanes) to give a clear
oil (45.2 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.32H.sub.36ClN.sub.2O.sub.3: 531.23. found: 531.68.
[1033] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-2-yl)quinolin-
-6-yl)ethanol: To a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-2-yl)quinolin-
-6-yl)ethyl pivalate (45.2 mg, 0.085 mmol) in tetrahydrofuran and
methanol (5:1, 1 mL) was added 1 M sodium hydroxide (2 mL) and the
reaction was heated to 45.degree. C. overnight. The reaction was
cooled to room temperature, diluted with water and extracted with
ethyl acetate. The organic layer was washed with brine, dried over
sodium sulfate and concentrated. The crude extract was
co-evaporated two times with acetonitrile to give a clear oil (33.8
mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.27H.sub.28ClN.sub.2O.sub.2: 447.18. found: 447.72.
[1034] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-2-yl)quinolin-
-6-yl)acetic acid (79): To a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-2-yl)quinolin-
-6-yl)ethanol (33.8 mg, 0.076 mmol) in wet acetonitrile at
0.degree. C. was added 0.4 M CrO.sub.3/H.sub.5IO.sub.6 (1.13 mL,
0.454 mmol) and the reaction was stirred at 0.degree. C. for 2
hours. The reaction was quenched with 1 M
NaH.sub.2PO.sub.42H.sub.2O and extracted with ethyl acetate. The
organic layer was concentrated and purified by reverse phase HPLC
(Gemini, 10-70% ACN/H.sub.2O+0.1% TFA) and the desired product was
lyophilized to give a white amorphous powder (5.1 mg). .sup.1H-NMR:
400 MHz, (CD.sub.3CN): 8.77 (d, J=4.4 Hz, 1H), 8.62 (d, J=8.0 Hz,
1H), 8.31 (d, J=8.8 Hz, 1H), 8.15 (t, J=7.0 Hz, 1H), 8.01 (s, 1H),
7.86 (d, J=8.8 Hz, 1H), 7.59 (m, 4H), 7.36 (d, J=8.4 Hz, 1H), 5.26
(s, 1H), 2.65 (s, 3H), 0.98 (s, 9H).
[1035] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.27H.sub.26ClN.sub.2O.sub.3: 461.16. found: 461.91.
Example 80
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(pyridin-2-yl)quinolin-6-yl)acetic acid (80)
##STR00212##
[1037]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(pyridin-2-yl)quinolin-6-yl)acetic acid (80) was
prepared following the procedure for
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-2-yl)quinolin-
-6-yl)acetic acid of Example 79 except that
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
was used instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate, a catalytic amount of lithium
chloride was used during the first step and the final step was
stirred for 1 hour. .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.:
8.72 (d, J=4.4 Hz, 1H), 8.63 (m, 2H), 8.23 (d, J=8.8 Hz, 1H), 8.11
(s, 1H), 8.07 (t, J=7.6 Hz, 1H), 7.70 (d, H=8.0 Hz, 1H), 7.54 (t,
J=4.8 Hz, 1H), 7.50 (d, J=4.8 Hz, 1H), 7.47 (d, J=9.2 Hz, 1H), 7.28
(d, J=8 Hz, 1H), 5.22 (s, 1H), 4.62 (m, 2H), 3.47 (t, J=6.0, 2H),
2.75 (s, 3H), 0.92 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+11].sup.+
calcd for C.sub.32H.sub.30N.sub.3O.sub.4: 520.22. found:
520.23.
Example 81
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(pyridin-3-yl)quinolin-6-yl)acetic acid (81)
##STR00213##
[1039]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(pyridin-3-yl)quinolin-6-yl)acetic acid (81) was
prepared following the procedure use for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(1H-pyrazol-5-yl)quinolin-6-yl)acetic acid of Example 71
except that pyridin-3-ylboronic acid was used instead of
1H-pyrazol-5-ylboronic acid. .sup.1H-NMR: 400 MHz, (CD.sub.3CN)
.delta.: 8.73 (d, J=7.4 Hz, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.58 (m,
1H), 8.38 (br s, 1H), 7.68 (m, 3H), 7.51 (m, 2H), 7.40 (d, J=8.8
Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 5.05 (s, 1H), 4.55 (m, 2H), 3.43
(t, J=6.0 Hz, 2H), 2.62 (s, 3H), 0.88 (s, 9H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.32H.sub.30N.sub.3O.sub.4:
520.22. found: 520.22.
Example 82
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1-methyl-1H-imidazol-5-
-yl)quinolin-6-yl)acetic acid (82)
##STR00214##
[1041]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1-methyl-1H-imi-
dazol-5-yl)quinolin-6-yl)acetic acid (82) was prepared following
the procedure for
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-2-yl)quinolin-
-6-yl)acetic acid of Example 79 except that
1-methyl-5-(tributylstannyl)-1H-imidazole was used instead of
2-(tributylstannyl)pyridine, a catalytic amount of lithium chloride
was used in the first step and the final reaction was stirred for 3
hours. .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 8.47 (s, 1H),
7.91 (s, 1H), 7.85 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.58 (s, 2H),
7.54 (t, J=8.0 Hz, 2H), 7.31 (d, J=8.4 Hz, 1H), 5.22 (s, 1H), 4.27
(s, 3H), 2.61 (s, 3H), 0.96 (s, 9H). LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.26H.sub.27ClN.sub.3O.sub.3: 464.17.
found: 464.51.
Example 83
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(1-methyl-1H-imidazol-5-yl)quinolin-6-yl)acetic acid
(83)
##STR00215##
[1043]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(1-methyl-1H-imidazol-5-yl)quinolin-6-yl)acetic acid
(83) was prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(pyridin-2-yl)quinolin-6-yl)acetic acid of Example 80
except that 1-methyl-5-(tributylstannyl)-1H-imidazole was used
instead of 2-(tributylstannyl)pyridine, the first reaction was run
for 25 minutes and using a catalytic amount of lithium chloride,
and the second step was stirred at room temperature over the
weekend instead of overnight at 45.degree. C. .sup.1H-NMR: 400 MHz,
(CD.sub.3CN) .delta.: 8.66 (d, J=4.8 Hz, 1H), 8.34 (s, 1H), 8.02
(s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.47 (d, J=5.2 Hz,
1H), 7.38 (s, 2H), 7.24 (d, J=7.6 Hz, 1H), 5.14 (s, 1H), 4.59 (m,
2H), 4.27 (s, 3H), 3.45 (t, J=5.6 Hz, 2H), 2.74 (s, 3H), 0.92 (s,
9H). LCMS-ESI.sup.F (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.31N.sub.4O.sub.4: 523.23. found: 523.28.
Example 84
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(1-methyl-1H-imidazol-2-yl)quinolin-6-yl)acetic acid
(84)
##STR00216##
[1045]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(1-methyl-1H-imidazol-2-yl)quinolin-6-yl)acetic acid
(84) was prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(pyridin-2-yl)quinolin-6-yl)acetic acid of Example 80
except using 1-methyl-2-(tributylstannyl)-1H-imidazole instead of
2-(tributylstannyl)pyridine, using a catalytic amount of lithium
chloride in the first step, and the second step was run at room
temperature over the weekend instead of at 45.degree. C. overnight.
.sup.1H-NMR: 400 MHz, (CD.sub.3CN). .delta.: 8.63 (d, J=4.8 Hz,
1H), 8.12 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H),
7.47 (m, 4H), 7.25 (d, J=8.0 Hz, 1H), 5.25 (s, 1H), 4.60 (m, 2H),
4.30 (s, 3H), 3.45 (t, J=5.6 Hz, 2H), 2.75 (s, 3H), 0.92 (s, 9H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.31N.sub.4O.sub.4: 523.23. found: 523.12.
Example 85
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(1-methyl-1H-imidazol-4-yl)quinolin-6-yl)acetic acid
(85)
##STR00217##
[1047]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(1-methyl-1H-imidazol-4-yl)quinolin-6-yl)acetic acid
(85) was prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(pyridin-2-yl)quinolin-6-yl)acetic acid of Example 80
except that 1-methyl-4-(tributylstannyl)-1H-imidazole was used
instead of 2-(tributylstannyl)pyridine, and a catalytic amount of
lithium chloride was used in the first step as well as being heated
for 25 minutes. The second step was run at room temperature over
the weekend, followed by at 45.degree. C. for four hours.
.sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 8.64 (d, J=4.8 Hz, 1H),
8.35 (s, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.58 (d, J=8.0 Hz, 1H),
7.47 (m, 2H), 7.36 (d, J=8.8 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 5.17
(s, 1H), 4.61 (m, 2H), 3.85 (s, 3H), 3.46 (t, J=6.0 Hz, 2H), 2.67
(s, 3H), 0.88 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.31N.sub.4O.sub.4: 523.23. found: 523.28.
Example 86
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1-methyl-1H-imidazol-4-
-yl)quinolin-6-yl)acetic acid (86)
##STR00218##
[1049]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1-methyl-1H-imi-
dazol-4-yl)quinolin-6-yl)acetic acid (86) was prepared following
the procedure for
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyridin-2-yl)quinolin-
-6-yl)acetic acid of Example 79 except that
1-methyl-4-(tributylstannyl)-1H-imidazole was used instead of
2-(tributylstannyl)pyridine, a catalytic amount of lithium chloride
was used in the first step, as well as being heated for 25 minutes
instead of 20 minutes. In the final step the reaction was stirred
for 4 hours.
[1050] .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 8.34 (s, 1H),
8.04 (s, 1H), 7.74 (s, 1H), 7.55 (m, 5H), 7.25 (d, J=8.0 Hz, 1H),
5.16 (s, 1H), 3.87 (s, 3H), 2.52 (s, 3H), 0.93 (s, 9H).
[1051] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.26H.sub.27ClN.sub.3O.sub.3: 464.17. found: 464.48.
Example 87
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyrimidin-5-yl)quinoli-
n-6-yl)acetic acid: (87)
##STR00219##
[1053]
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(pyrimidin-5-yl)-
quinolin-6-yl)acetic acid (87) was prepared following the procedure
used for
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(1H-pyrazol-5-yl)q-
uinolin-6-yl)acetic acid of Example 70 except that
pyrimidin-5-ylboronic acid was used instead of
1H-pyrazol-5-ylboronic acid. .sup.1H-NMR: 400 MHz, (CD.sub.3CN)
.delta.: 9.52 (br s, 2H), 9.26 (s, 1H), 8.00 (s, 1H), 7.90 (d,
J=8.8 Hz, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.60 (m, 3H), 7.37 (d, J=7.6
Hz, 1H), 5.27 (s, 1H), 2.65 9s, 3H), 0.99 (s, 9H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.26H.sub.25ClN.sub.3O.sub.3:
462.15. found: 462.45.
Example 88
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(pyridazin-4-yl)quinolin-6-yl)acetic acid (88)
##STR00220##
[1055]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(pyridazin-4-yl)quinolin-6-yl)acetic acid (88) was
prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(pyridin-2-yl)quinolin-6-yl)acetic acid of Example 80
except that 4-(tributylstannyl)pyridazine was used instead of
2-(tributylstannyl)pyridine. The first step was run with a
catalytic amount of lithium chloride, and the last step required an
additional 1 mL of 0.4 M CrO.sub.3/H.sub.5IO.sub.6 and three drops
of water for completion. .sup.1H-NMR: 400 MHz, (CD.sub.3CN)S: 9.80
(br s, 1H), 9.24 (br s, 1H), 8.67 (d, J=4.8 Hz, 1H), 8.25 (s, 1H),
8.05 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.58
(d, J=4.4 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H),
5.22 (s, 1H), 4.64 (m, 2H), 3.52 (t, J=5.6 Hz, 2H), 2.76 (s, 3H),
0.94 (s, 9H).
[1056] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.29N.sub.4O.sub.4: 521.21. found: 521.18.
Example 89
(S)-2-tert-Butoxy-2-((R)-5-(5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6--
yl)-2,7-dimethylquinolin-6-yl)acetic acid (89)
##STR00221##
[1058] Preparation of (S)-ethyl
2-tert-butoxy-2-((R)-5-(5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-
-2,7-dimethylquinolin-6-yl)acetate: To a solution of (S)-ethyl
2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H) (50
mg, 0.126 mmol) and
5-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-b-
enzo[b][1,4]oxazine (74 mg, 0.252 mmol) in 1-methyl-2-pyrrolidinone
was added 2 M potassium carbonate (0.252 mL, 0.504 mmol) and
Pd(PPh.sub.3).sub.4 (15 mg, 0.013 mmol) and the reaction was
degassed with argon for 5 minutes. The reaction was heated to
110.degree. C. for 30 minutes in a microwave reactor. The crude
reaction was absorbed onto silica and purified by flash column
chromatography (silica gel, ethyl acetate/hexanes) to give a yellow
oil (44 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.27H.sub.32ClN.sub.2O.sub.4: 483.20;
[1059] found: 483.93.
[1060] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-
-yl)-2,7-dimethylquinolin-6-yl)acetic acid (89): To a solution of
(S)-ethyl
2-tert-butoxy-2-((R)-5-(5-chloro-3,4-dihydro-2H-benzo[b][1,4]ox-
azin-6-yl)-2,7-dimethylquinolin-6-yl)acetate (44 mg, 0.092 mmol) in
tetrahydrofuran:ethanol:water (2:2:1, 3 mL) was added lithium
hydroxide (11 mg, 0.459 mmol) and the reaction was heated to
45.degree. C. overnight. The crude material was purified by reverse
phase HPLC (Gemini, 10-48% ACN/H.sub.2O+0.1% TFA) and the desired
product was lyophilized to give a yellow powder (3.8 mg).
.sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 8.22 (s, 1H), 7.99 (d,
J=8.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.40
(d, J=8.0 Hz, 1H), 5.35 (s, 1H), 4.27 (m, 2H), 3.50 (t, J=4.2 Hz,
2H), 2.87 (s, 3H), 2.80 (s, 3H), 1.10 (s, 9H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.25H.sub.28ClN.sub.2O.sub.4:
455.17. found: 455.51.
Example 90
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-7-methylquinolin-6-yl)-
acetic acid (90)
##STR00222##
[1062] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-7-methylquinolin-6-yl-
)ethyl pivalate: To a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (200
mg, 0.33 mmol) and iron (III) acetylacetonate (6 mg, 0.017 mmol) in
anhydrous tetrahydrofuran/1-methyl-2-pyrrolidinone (5 mL/0.5 mL) at
0.degree. C. was added 2.9 M in tetrahydrofuran isopropylmagnesium
bromide (0.149 mL, 0.431 mmol) drop wise. The reaction was let warm
to room temperature over three hours, quenched with water and
extracted with ethyl acetate and concentrated. The crude reaction
was purified by flash column chromatography (silica gel, ethyl
acetate/hexanes) to give a yellow oil (77 mg). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.30H.sub.39ClNO.sub.3: 496.25.
found: 496.83.
[1063] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-7-methylquinolin-6-yl-
)ethanol: To a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-7-methylquinolin-6-yl-
)ethyl pivalate (77 mg, 0.156 mmol) in tetrahydrofuran/methanol
(2:1, 1 mL) was added 1 M sodium hydroxide (2 mL) and the reaction
was heated to 45.degree. C. overnight. The reaction mixture was
cooled to room temperature and diluted with water, extracted with
ethyl acetate and washed with brine. The organic layer was then
dried over sodium sulfate and concentrated, followed by
co-evaporation with acetonitrile to give a clear oil (62 mg).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.31ClNO.sub.2: 412.20. found: 412.96.
[1064] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-7-methylquinolin-6-yl-
)acetic acid (90): To a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-isopropyl-7-methylquinolin-6-yl-
)ethanol (62 mg, 0.149 mmol) in wet acetonitrile at 0.degree. C.
was added 0.4 M CrO.sub.3/H.sub.5IO.sub.6 (2.24 mL, 0.897 mmol)
drop wise and stirred at 0.degree. C. for 3 hours. Reaction was
quenched with 2 M NaH.sub.2PO.sub.42H.sub.2O and purified by
reverse phase HPLC (Gemini, 15-56% ACN/H.sub.2O+0.1% TFA) and the
desired product lyophilized to give a white powder (38 mg).
[1065] .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 8.21 (s, 1H),
8.12 (d, J=9.2 Hz, 1H), 7.60 (m, 4H), 7.33 (d, J=7.6 Hz, 1H), 5.25
(s, 1H), 3.57 (dq, J=6.8, 6.4 Hz, 1H), 2.68 (s, 3H), 1.42 (d, J=6.8
Hz, 3H), 1.41 (d, J=6.4 Hz, 3H), 0.97 (s, 9H).
[1066] LCMS-ESI (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.29ClNO.sub.3: 426.18. found: 426.78.
Example 91
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-7-methylquino-
lin-6-yl)acetic acid (91)
##STR00223##
[1068] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-7-methylquin-
olin-6-yl)ethyl pivalate: To a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26) (200
mg, 0.332 mmol) in 1,2-dimethoxyethane was added imidazole (226 mg,
3.32 mmol) and the reaction was sealed and heated to 95.degree. C.
overnight. The crude reaction mixture was absorbed onto silica gel
and purified by flash column chromatography (silica gel, ethyl
acetate/hexanes) to give a yellow oil (33.2 mg). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.30H.sub.35ClN.sub.3O.sub.3:
520.23. found: 520.35.
[1069] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-7-methylquin-
olin-6-yl)ethanol: To a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-7-methylquin-
olin-6-yl)ethyl pivalate (39.2 mg, 0.075 mmol) in tetrahydrofuran
and methanol (5:1, 1 mL) was added 1 M sodium hydroxide (2 mL) and
the reaction was heated to 45.degree. C. overnight. The reaction
was cooled to room temperature, diluted with water and extracted
with ethyl acetate. The organic layer was washed with brine, dried
over sodium sulfate and concentrated. The crude extract was
co-evaporated two times with acetonitrile to give a clear white oil
(32.1 mg). LCMS-ER.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.27ClN.sub.3O.sub.2: 436.17. found: 436.86.
[1070] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-7-methylquin-
olin-6-yl)acetic acid (91): To a solution of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-7-methylquin-
olin-6-yl)ethanol (32.1 mg, 0.074 mmol) in wet acetonitrile at
0.degree. C. was added 0.4 M CrO.sub.3/H.sub.5IO.sub.6 (1.1 mL,
0.442 mmol) and the reaction was stirred at 0.degree. C. for three
hours. The reaction was quenched with 1 M
NaH.sub.2PO.sub.42H.sub.2O and extracted with ethyl acetate. The
organic layer was concentrated and purified by reverse phase HPLC
(Gemini, 10-55% ACN/H.sub.2O+0.1% TFA) and the desired product
lyophilized to give a white amorphous powder (11.1 mg).
[1071] .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 9.15 (s, 1H),
8.13 (s, 1H), 7.87 (m, 2H), 7.58 (m, 4H), 7.51 (s, 1H), 7.33 (d,
J=8 Hz, 1H), 5.24 (s, 1H), 2.62 (s, 3H), 0.97 (s, 9H).
[1072] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.25ClN.sub.3O.sub.3: 450.15. found: 450.59.
Example 92
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(i-
sobutyl(methyl)amino)-7-methylquinolin-6-yl)acetic acid (92)
##STR00224##
[1074]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-2-(isobutyl(methypamino)-7-methylquinolin-6-yl)acetic acid (92)
was prepared following the procedure for
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-7-methylquin-
olin-6-yl)acetic acid of Example 91 except that
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate
was used instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfon-
yloxy)quinolin-6-yl)ethyl pivalate and N,2-dimethylpropan-1-amine
was used instead of imidazole. .sup.1H-NMR: 400 MHz, (CD.sub.3CN)
.delta.: 8.65 (d, J=4.8 Hz, 1H), 7.96 (s, 1H), 7.52 (d, J=7.6 Hz,
1H), 7.41 (d, J=4.8 Hz, 1H), 7.26 (d, J=10.0 Hz, 1H), 7.18 (d,
J=7.6 Hz, 1H), 6.89 (d, J=9.6 Hz, 1H), 5.12 (s, 1H), 4.57 (m, 2H),
3.48 (m, 2H), 3.40 (t, J=5.2 Hz, 2H), 3.34 (s, 3H), 2.68 (s, 3H),
2.09 (m, 1H), 0.93 (m, 6H), 0.86 (s, 9H).
[1075] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.32H.sub.38N.sub.3O.sub.4: 528.28. found: 528.34.
Example 93
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(e-
thyl(methyl)amino)-7-methylquinolin-6-yl)acetic acid (93)
##STR00225##
[1077]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-2-(ethyl(methypamino)-7-methylquinolin-6-yl)acetic acid (93) was
prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
isobutyl(methyl)amino)-7-methylquinolin-6-yl)acetic acid of Example
92 except that N-ethyl-N-methylamine was used instead of
N,2-dimethylpropan-1-amine. .sup.1H-NMR: 400 MHz, (CD.sub.3CN)
.delta.: 8.64 (d, J=4.4 Hz, 1H), 7.96 (s, 1H), 7.51 (d, J=7.6 Hz,
1H), 7.39 (d, J=4.8 Hz, 1H), 7.25 (d, J=9.6 Hz, 1H), 7.17 (d, J=8.0
Hz, 1H), 6.84 (d, J=9.6 Hz, 1H), 5.11 (s, 1H), 4.57 (m, 2H), 3.71
(m, 2H), 3.40 (t, J=5.6 Hz, 2H), 3.31 (s, HI), 2.66 (s, 3H), 1.23
(t, J=7.2 Hz, 3H), 0.85 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calcd for C.sub.30H.sub.34N.sub.3O.sub.4: 500.25. found:
500.32.
Example 94
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(pyrrolidin-1-yl)quinolin-6-yl)acetic acid (94)
##STR00226##
[1079]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(pyrrolidin-1-yl)quinolin-6-yl)acetic acid (94) was
prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
isobutyl(methyl)amino)-7-methylquinolin-6-yl)acetic acid in of
Example 92 except that pyrrolidine was used instead of
N,2-dimethylpropan-1-amine. .sup.1H-NMR: 400 MHz, (CD.sub.3CN)
.delta.: 8.64 (d, 4.8 Hz, 1H), 7.91 (s, 1H), 7.52 (d, J=7.2 Hz,
1H), 7.39 (d, J=4.4 Hz, 1H), 7.24 (d, J=10.0 Hz, 1H), 7.17 (d,
J=8.0 Hz, 1H), 6.71 (d, J=10.0 Hz, 1H), 5.11 (s, 1H), 4.57 (m, 2H),
3.74 (m, 2H), 3.60 (m, 2H), 3.40 (t, J=6.0 Hz, 2H), 2.66 (s, 3H),
2.09 (m, 4H), 0.85 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd
for C.sub.31H.sub.34N.sub.3O.sub.4: 512.25. found: 512.18.
Example 95
(S)-2-((R)-2-(azetidin-1-yl)-5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic acid
(95)
##STR00227##
[1081] (S)-2-((R)-2-(Azetidin-1-yl)-5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-7-methylquinolin-6-yl)-2-tert-butoxyacetic acid (95)
was prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
isobutyl(methypamino)-7-methylquinolin-6-yl)acetic acid of Example
92 except that azetidine was used instead of
N,2-dimethylpropan-1-amine.
[1082] .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 8.63 (d, (J=4.4
Hz, 1H), 7.77 (s, 1H), 7.50 (m, 1H), 7.38 (d, 4.4 Hz, 1H), 7.19 (d,
J=10.4 Hz, 1H), 7.16 (d, 8.0 Hz, 1H), 6.41 (d, 10.0 Hz, 1H), 5.10
(s, 1H), 4.56 (m, 2H), 4.40 (m, 4H), 3.39 (t, J=6.4 Hz, 2H), 2.65
(s, 3H), 2.51 (p, J=7.6 Hz, 2H), 0.85 (s, 9H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.30H.sub.32N.sub.3O.sub.4:
498.23. found: 498.14.
Example 96
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(d-
imethylamino)-7-methylquinolin-6-yl)acetic acid (96)
##STR00228##
[1084]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-2-(dimethylamino)-7-methylquinolin-6-yl)acetic acid (96) was
prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
isobutyl(methypamino)-7-methylquinolin-6-yl)acetic acid of Example
92 except that dimethylamine was used instead of
N,2-dimethylpropan-1-amine.
[1085] .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 8.63 (d, J=4.8
Hz, 1H), 7.96 (s, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.39 (d, J=4.4 Hz,
1H), 7.26 (d, J=9.6 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 6.83 (d,
J=10.4 Hz, 1H), 5.12 (s, 1H), 4.57 (m, 2H), 3.39 (t, J=6.8 Hz, 2H),
3.32 (s, 6H), 2.66 (s, 3H), 0.86 (s, 9H). LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.29H.sub.32N.sub.3O.sub.4: 486.23.
found: 486.25.
Example 97
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-oxo-1,2-dihydroquinolin-6-yl)acetic acid (97)
##STR00229##
[1087] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-oxo-1,2-dihydroquinolin-6-yl)acetic acid (97): Compound 97
was isolated as a side product of the synthesis of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
1H-imidazol-1-yl)-7-methylquinolin-6-yl)acetic acid (compound 98 of
Example 98). .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 8.69 (d,
J=5.2 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.54 (d, J=4.8 Hz, 1H), 7.26
(d, J=4.0 Hz, 1H), 7.24 (s, 1H), 6.87 (d, J=9.6 Hz, 1H), 6.19
(J=9.6 Hz, 1H), 5.03 (s, 1H), 4.59 (m, 2H), 3.47 (t, J=5.6 Hz, 2H),
2.59 (s, 3H), 0.87 (s, 9H). LCMS-ESI.sup.+ (m/z):
[1088] [M+H].sup.+ calcd for C.sub.27H.sub.27N.sub.2O.sub.5:
459.51. found: 459.20.
Example 98
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(1-
H-imidazol-1-yl)-7-methylquinolin-6-yl)acetic acid (98)
##STR00230##
[1090]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-2-(1H-imidazol-1-yl)-7-methylquinolin-6-yl)acetic acid (98) was
prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
isobutyl(methypamino)-7-methylquinolin-6-yl)acetic acid of Example
92 except that imidazole was used instead of
N,2-dimethylpropan-1-amine and the last step had an additional 6
equivalents of 0.4 CrO.sub.3/H.sub.5IO.sub.6 added 2 hours into the
reaction and was then stirred an additional 3 hours. .sup.1H-NMR:
400 MHz, (CD.sub.3CN) .delta.: 9.16 (s, 1H), 8.63 (d, J=4.4 Hz,
1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.59 (d, J=14.8 Hz, 1H), 7.53 (m,
3H), 7.42 (d, J=4.8 Hz, 1H), 5.22 (s, 1H), 4.59 (m, 2H), 3.43 (t,
J=6.0 Hz, 2H), 2.74 (s, 3H), 0.91 (s, 9H). LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.30H.sub.29N.sub.4O.sub.4: 509.21.
found: 509.14.
Example 99
(S)-2-tert-butoxy-2-((R)-2-(difluoromethyl)-5-(2,3-dihydropyrano[4,3,2-de]-
quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (99)
##STR00231## ##STR00232##
[1092] Preparation of
(S)-5-bromo-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-2,7-dimethylquinoline
1-oxide: To a solution of (S)-ethyl
2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H)
(500 mg, 1.27 mmol) in dichloromethane (13 mL) at 0.degree. C. was
added 3-chloroperoxybenzoic acid (269 mg, 77%, 1.21 mmol) and the
reaction mixture was allowed to slowly warm to room temperature
over 3 hours. The reaction mixture was partitioned between ethyl
acetate and water and the organic layer was concentrated and
purified by flash column chromatography (silica gel, ethyl
acetate/hexanes and methanol/ethyl acetate) to give a yellow oil
(497 mg, 95%). LCMS-ESI.sup.+ (m/z): [M].sup.+ calcd for
C.sub.19H.sub.2413rNO.sub.4: 410.3;
[1093] found: 410.8.
[1094] Preparation of (S)-ethyl
2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate:
A solution of
S)-5-bromo-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-2,7-dimethylquinoline
1-oxide (497 mg, 1.21 mmol) in acetic acid (12 mL) was heated at
80.degree. C. for 15 minutes. To the solution was added acetic
anhydride (1.37 mL, 14.5 mmol) and the resulting solution was
heated at 110.degree. C. for 2 hours. The reaction mixture was
cooled to 50.degree. C. and methanol (6 mL) was added and stirred
for 1 hour. The reaction was cooled to room temperature and
concentrated. The resultant oil was taken up in tetrahydrofuran (20
mL) to which was added 6 M potassium hydroxide (20 mL) and stirred
for 1 hour. The product was extracted with ethyl acetate and the
organic layer was concentrated and purified by flash column
chromatography (silica gel, ethyl acetate/hexanes) to give a yellow
oil (366 mg, 74%). LCMS-ESI.sup.+ (m/z):
[1095] [M+H].sup.+ calcd for C.sub.19H.sub.25BrNO.sub.4: 411.3.
found: 410.7.
[1096] Preparation of (S)-ethyl
2-(5-bromo-2-formyl-7-methylquinolin-6-yl)-2-tert-butoxyacetate: To
a solution of (S)-ethyl
2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate
(200 mg, 0.49 mmol) in anhydrous dichloromethane (13 mL) at
0.degree. C. was added Dess-Martin periodinane (248 mg, 0.58 mmol)
and the reaction mixture was stirred for 1 hour. Reaction mixture
was partitioned between dichloromethane and water and organic layer
was concentrated and purified by flash column chromatography
(silica gel, ethyl acetate/hexanes) to give a white solid (160 mg,
80%). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.19H.sub.23BrNO.sub.4: 408.07. found: 408.88, 410.14
[1097] Preparation of (S)-ethyl
2-(5-bromo-2-(difluoromethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate-
: To a solution of Fluolead (392 mg, 1.57 mmol) in anhydrous
dichloromethane (2 mL) at 0.degree. C. was added (S)-ethyl
2-(5-bromo-2-formyl-7-methylquinolin-6-yl)-2-tert-butoxyacetate
(160 mg, 0.39 mmol) as a solution in anhydrous dichloromethane (2
mL) and the reaction mixture was allowed to slowly warm to room
temperature overnight. The reaction mixture was quenched with 0.5 M
sodium hydroxide (10 mL), stirred 1 hour, and then partitioned
between dichloromethane and 0.5 M sodium hydroxide and organic
layer was concentrated and purified by flash column chromatography
(silica gel, ethyl acetate/hexanes) to give a white solid (137 mg,
81%). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.19H.sub.23BrNO.sub.4: 430.08. found: 430.61, 431.85.
[1098] Preparation of (S)-ethyl
2-tert-butoxy-2-((R)-2-(difluoromethyl)-5-(2,3-dihydropyrano[4,3,2-de]qui-
nolin-7-yl)-7-methylquinolin-6-yl)acetate: To a solution of
(S)-ethyl
2-(5-bromo-2-(difluoromethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate
(70 mg, 0.16 mmol) in 1,2-dimethoxyethane (2 mL) was added
2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HCl salt (82
mg, 0.325 mmol), 2 M potassium carbonate (0.326 mL, 0.65 mmol) and
Pd(PPh.sub.3).sub.4 (19 mg, 0.016 mmol). The reaction mixture was
sparged with argon for 5 minutes and then heated in microwave at
100.degree. C. for 40 minutes. The reaction mixture was absorbed
onto silica and purified by flash column chromatography (silica
gel, ethyl acetate/hexanes) to give a brown film (35 mg, 41%).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.30H.sub.31F.sub.2N.sub.2O.sub.4: 521.22. found: 521.20.
[1099] Preparation of
(S)-2-tert-butoxy-2-((R)-2-(difluoromethyl)-5-(2,3-dihydropyrano[4,3,2-de-
]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (99): To a
solution of (S)-ethyl
2-tert-butoxy-2-((R)-2-(difluoromethyl)-5-(2,3-dihydropyrano[4,-
3,2-de]quinolin-7-yl)-7-methylquinolin-6-ypacetate (35 mg, 0.07
mmol) in 1:1 tetrahydrofuran and ethanol (2.4 mL) was added lithium
hydroxide (8 mg, 0.34 mmol) in 0.6 mL of water. The reaction was
heated to 45.degree. C. overnight. The reaction mixture was
purified by reverse phase HPLC (Gemini, 15 to 55% ACN/H.sub.2O+0.1%
TFA) and the desired product was lyophilized to give a yellow
powder (15.9 mg). .sup.1H-NMR: 400 MHz, (CD.sub.3CN): 8.63 (d,
J=4.8 Hz, 1H), 8.10 (s, 1H), 7.71 (d, J=8 Hz, 1H), 7.54 (d, J=5.2
Hz, 1H), 7.48 (s, 2H), 7.30 (d, J=8 Hz, 1H), 6.83 (t,
J.sub.H--F=55.2 Hz, 1H), 5.22 (s, 1H), 4.61 (m, 2H), 3.49 (t, J=6
Hz, 2H), 2.75 (s, 3H), 0.91 (s, 9H). LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.28H.sub.27F.sub.2N.sub.2O.sub.4:
493.19. found: 493.12.
Example 100
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(difluoromethyl)-7-methylquinoli-
n-6-yl)acetic acid (100)
##STR00233## ##STR00234##
[1101] Preparation of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-ypacetate:
To a solution of (S)-ethyl
2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H)
(500 mg, 1.27 mmol) and 4-chlorophenylboronic acid (238 mg, 1.52
mmol) in 1,2-dimethoxyethane (8 mL) was added Pd(PPh.sub.3).sub.4
(147 mg, 0.13 mmol) and 2 M potassium carbonate (1.91 mL). The
reaction was degassed for 15 minutes with argon and then heated to
110.degree. C. for 20 minutes in a microwave reactor. The crude
reaction was absorbed onto silica and purified by flash column
chromatography (silica gel, ethyl acetate/hexanes) to give a pink
foam (489 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.29ClNO.sub.3: 426.18;
[1102] found: 426.75.
[1103] Preparation of
(S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethyl-
quinoline 1-oxide: To a solution of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2,7-dimethylquinolin-6-yl)acetate
(489 mg, 1.15 mmol) in anhydrous dichloromethane at 0.degree. C.
was added 3-chloroperoxybenzoic acid (243 mg, 77%, 1.09 mmol) and
the reaction was stirred for 3 h. The crude reaction was absorbed
onto silica gel and purified by flash column chromatography (silica
gel, ethyl acetate/hexanes, methanol/ethyl acetate) to give a white
foam (261 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.29ClNO.sub.4: 442.17. found: 442.88.
[1104] Preparation of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(hydroxymethyl)-7-methylquinolin-6--
ypacetate: A solution of
(S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethyl-
quinoline 1-oxide (261 mg, 0.59 mmol) in acetic acid (6 mL) was
heated to 80.degree. C. for 15 minutes. To the solution was added
acetic anhydride (0.67 mL, 7.09 mmol) and the resulting solution
was heated at 110.degree. C. for 2 hours. The reaction mixture was
cooled to 50.degree. C. and 3 mL of methanol was added and stirred
for 1 hour. The reaction was cooled to room temperature and
concentrated. The resultant oil was taken up in tetrahydrofuran and
6 M potassium hydroxide was added to adjust to pH 12 and stirred
for 3 hours. The mixture was then diluted with water and extracted
with ethyl acetate and concentrated. The product was purified by
flash column chromatography (silica gel, ethyl acetate/hexanes) to
give a clear oil (213 mg).
[1105] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.29ClNO.sub.4: 442.17. found: 442.69.
[1106] Preparation of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-formyl-7-methylquinolin-6-ypacetate-
: To a solution of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(hydroxymethyl)-7-methylquinolin-6--
ypacetate (160 mg, 0.36 mmol) in anhydrous dichloromethane at
0.degree. C. was added Dess-Martin periodinane (184 mg, 0.43 mmol)
and the reaction was stirred for 1 hour at 0.degree. C. The
reaction was quenched with water, extracted with dichloromethane
and concentrated. The crude product was purified by flash column
chromatography (silica gel, ethyl acetate/hexanes) to give a clear
oil (139 mg). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.25H.sub.27ClNO.sub.4: 440.16. found: 440.55.
[1107] Preparation of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(difluoromethyl)-7-methylquinolin-6-
-ypacetate: To a solution of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-formyl-7-methylquinolin-6-ypacetate
(139 mg, 0.32 mmol) in anhydrous dichloromethane (3 mL) at
0.degree. C. was added Fluolead (174 mg, 0.695 mmol) and the
reaction was stirred for 1/2 hour at 0.degree. C. and then allowed
to warm to room temperature overnight. The reaction was quenched
with 0.5 M sodium hydroxide and stirred for 1 hour. The crude
product was extracted with dichloromethane, concentrated and
purified by flash column chromatography (silica gel, ethyl
acetate/hexanes) to give a clear oil (111 mg). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.25H.sub.27ClF.sub.2NO.sub.3:
462.16. found: 462.54.
[1108] Preparation of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(difluoromethyl)-7-methylquinol-
in-6-yl)acetic acid (100): To a solution of (S)-ethyl
2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(difluoromethyl)-7-methylquinolin-6-
-ypacetate (111 mg, 0.24 mmol) in tetrahydrofuran:ethanol:water
(2:2:1, 3 mL) was added lithium hydroxide (29 mg, 1.2 mmol) and the
reaction was heated to 45.degree. C. overnight. The crude product
was purified by reverse phase HPLC (Gemini, 20-29%
ACN/H.sub.2O+0.1% TFA) and the desired product was lyophilized to
give a white powder (77.5 mg).
[1109] .sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 7.97 (s, 1H),
7.87 (d, J=8.8 Hz, 1H), 7.59 (m, 4H), 7.35 (d, J=7.6 Hz, 1H), 6.84
(t, J.sub.H--F=55.2 Hz, 1H), 5.26 (s, 1H), 2.64 (s, 3H), 0.97 (s,
9H). .sup.19F-NMR: 377 MHz, (CD.sub.3CN) 8: -116.71 (dd, J=62.02,
55.42 Hz).
[1110] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.23H.sub.23ClF.sub.2NO.sub.3: 434.88. found: 434.47.
Example 101
(S)-2-(1-(2-(((9H-Fluoren-9-yl)methoxy)carbonylamino)ethyl)-5-(4-chlorophe-
nyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyacetic
acid (101)
##STR00235## ##STR00236##
[1112] Preparation of
(S)-6-(1-tert-butoxy-2-(tert-butyldimethylsilyloxy)ethyl)-5-(4-chlorophen-
yl)-7-methylquinolin-2(1H)-one: To a solution of
(S)-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin--
2(1H)-one (8K) (0.5175 g, 1.34 mmol) in DMF (5.0 mL), was added
imidazole (0.204 g, 4.02 mmol), followed by tert-butyldimethylsilyl
chloride (0.243 g, 1.61 mmol) at 0.degree. C. The reaction mixture
was warmed to room temperature overnight. Additional imidazole (0.2
g) and tert-butyldimethylsilyl chloride (0.30 g) were added and the
mixture stirred for another 2 hours. The reaction mixture was the
diluted with ethyl acetate, washed with 5% lithium chloride
solution (2.times.), brine, dried (MgSO.sub.4), filtered,
concentrated and purified by flash column chromatography (silica
gel, 20 to 60% ethyl acetate/hexanes) to give a yellow foam (0.500
g). LCMS-ESI.sup.+ (m/z): calcd for C.sub.28H.sub.39ClNO.sub.3Si:
501.1;
[1113] found: 500.3, 502.2.
[1114] Preparation of (S)-2-(trimethylsilyl)ethyl
2-(6-(1-tert-butoxy-2-(tert-butyldimethylsilyloxy)ethyl)-5-(4-chloropheny-
l)-7-methyl-2-oxoquinolin-1(2H)-yl)ethylcarbamate: To a solution of
(S)-6-(1-tert-butoxy-2-(tert-butyldimethylsilyloxy)ethyl)-5-(4-chlorophen-
yl)-7-methylquinolin-2(1H)-one (0.4061 g, 0.812 mmol) in DMF (8.0
mL) was added potassium tert-butoxide (0.137 g, 1.22 mmol) and the
mixture stirred for 30 minutes. A solution of
2-(trimethylsilyl)ethyl 2-bromoethylcarbamate (0.327 g, 1.22 mmol)
in DMF (1 mL) was added and the reaction mixture was allowed to
slowly warm to room temperature overnight. The reaction mixture was
cooled to 0.degree. C., potassium tert-butoxide (0.200 g) was added
and the resulting reaction mixture was stirred for 30 minutes. A
solution of 2-(trimethylsilyl)ethyl 2-bromoethylcarbamate (0.5 g)
in DMF (1 mL) was added and the reaction mixture was warmed to room
temperature overnight. Reaction mixture was diluted with ethyl
acetate and washed with 5% lithium chloride solution (2.times.),
brine, dried (MgSO.sub.4), filtered, concentrated and purified by
flash column chromatography (silica gel, 10 to 50% ethyl
acetate/hexanes) to give desired product a yellow foam (0.2725 g).
Some O-alkylation side-product was also observed.
[1115] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.36H.sub.56ClN.sub.2O.sub.5Si.sub.2: 688.5. found: 687.1,
689.1.
[1116] Preparation of (S)-(9H-fluoren-9-yl)methyl
2-(6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methyl-2-oxoquin-
olin-1(2H)-yl)ethylcarbamate: To a solution of
(S)-2-(trimethylsilyl)ethyl
2-(6-(1-tert-butoxy-2-(tert-butyldimethylsilyloxy)ethyl)-5-(4-chloropheny-
l)-7-methyl-2-oxoquinolin-1(2H)-yl)ethylcarbamate (0.456 g, 0.663
mmol) in THF (6.6 mL) at 0.degree. C. was added 1 M TBAF in THF
(1.99 mL, 1.99 mmol) and reaction mixture was warmed to room
temperature overnight. Reaction mixture was cooled to 0.degree. C.,
additional 1 M TBAF in THF (1.0 mL, 1.0 mmol) was added and warmed
to room temperature over 8 hours. Reaction mixture was cooled to
0.degree. C., saturated sodium bicarbonate solution (1.0 mL) and
9-fluorenylmethoxycarbonyl chloride (0.257 g, 0.995 mmol) were
added. Reaction mixture was vigorously stirred overnight at room
temperature, diluted with ethyl acetate, washed with brine, dried
(MgSO.sub.4), filtered, concentrated and purified by flash column
chromatography (silica gel, 30 to 70% ethyl acetate/hexanes) to
give a white foam (0.389 g). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calcd for C.sub.39H.sub.40ClN.sub.2O.sub.5: 652.2. found: 651.2,
652.2, 653.2.
[1117] Preparation of
(S)-2-(1-(2-(((9H-fluoren-9-yOmethoxy)carbonylamino)ethyl)-5-(4-chlorophe-
nyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyacetic
acid (101): To a solution of (S)-(9H-fluoren-9-yl)methyl
2-(6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methyl-2-oxoquin-
olin-1(2H)-yl)ethylcarbamate (0.3443 g, 0.529 mmol) in
dichloromethane (5.0 mL) was added Dess-Martin periodinane (0.449
g, 1.06 mmol). Reaction mixture was allowed to warm to room
temperature over 1.5 hours, quenched with sodium thiosulfate
solution and extracted with ethyl acetate. Organic layer was washed
with brine, dried (MgSO.sub.4), filtered, concentrated and used in
next step without further purification. LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.39H.sub.38ClN.sub.2O.sub.5: 650.2.
found: 649.1, 650.1.
[1118] To a solution of the above residue in acetonitrile (5.0 mL)
and 1 M NaH.sub.2PO.sub.4 buffer (5.0 mL) was added 80% sodium
chlorite (0.44 g, 1.587 mmol). Reaction mixture was stirred for 1.5
hours, diluted with water and ethyl acetate. The pH was adjusted to
-pH 5 with 1 N HCl solution and organic layer was washed with
brine, dried (MgSO.sub.4), filtered, concentrated and purified by
flash column chromatography (silica gel, 0 to 10%
methanol/dichloromethane) to give a yellow powder (0.1943 g).
[1119] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.78 (d, J=7.6 Hz,
2H), 7.71 (s, 1H), 7.63 (dd, J=6.4, 6.4 Hz, 2H), 7.57-7.51 (m, 3H),
7.41-7.28 (m, 5H), 7.22 (d, J=7.2 Hz, 1H), 6.47 (d, J=10 Hz, 1H),
5.02 (s, 1H), 4.49 (dd, J=8.4, 8.4 Hz, 2H), 4.36-4.28 (m, 2H), 4.15
(dd, J=7.2, 7.2 Hz, 1H), 3.51-3.48 (m, 2H), 2.64 (s, 3H), 0.92 (s,
9H).
[1120] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.39H.sub.38ClN.sub.2O.sub.6: 666.2. found: 665.1, 666.1.
[1121] Preparation of 2-(trimethylsilyl)ethyl
2-bromoethylcarbamate: Trimethylsilylethyl chloroformate was
prepared according to Sekine et al, Lett. Org. Chem. 2004, 1,
179-182. To a mixture of 2-bromoethylamine hydrobromide (1.0 g,
4.88 mmol) in THF (20 mL) was added saturated sodium bicarbonate
solution, followed by crude trimethylsilylethyl chloroformate (8.8
g, 14.64 mmol). Reaction mixture was stirred overnight at room
temperature, concentrated and portioned between ethyl acetate and
saturated sodium bicarbonate solution. Aqueous layer was extracted
with ethyl acetate (2x) and combined organic layer was dried
(MgSO.sub.4), filtered, concentrated and purified by flash column
chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give
a colorless oil (1.321 g).
[1122] .sup.1H-NMR: 400 MHz, (CD.sub.3C1) .delta.: 4.14 (dd, J=8.4,
8.4 Hz, 2H), 3.74-3.69 (m, 2H), 3.55 (dd, J=5.6, 5.6 Hz, 2H), 3.44
(dd, J=5.6, 5.6 Hz, 2H), 0.99-0.92 (m, 2H), -0.008 (s, 9H).
Example 102
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydrobenzo[de]chromen-7-yl)-2,7-dimethyl-
quinolin-6-yl)acetic acid (102A) and
(S)-2-tert-butoxy-2-((S)-5-(2,3-dihydrobenzo[de]chromen-7-yl)-2,7-dimethy-
lquinolin-6-yl)acetic acid (102B)
##STR00237##
[1124] Preparation of (2S)-ethyl
2-tert-butoxy-2-(5-(2,3-dihydrobenzo[de]chromen-7-yl)-2,7-dimethylquinoli-
n-6-ypacetate: In a 5-10 mL microwave vial, (S)-ethyl
2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H)
(82.4 mg, 0.21 mmol) was dissolved in 4.0 mL of DMA. To this was
added
2-(2,3-dihydrobenzo[de]chromen-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborol-
ane (110 mg, 0.37 mmol), Pd(PPh.sub.3).sub.4 (24.2 mg, 0.021 mmol)
and 225 .mu.L of 2 M K.sub.2CO.sub.3, the reaction vessel sealed
and heated thermally at 80.degree. C. for 4 hours. The mixture was
diluted 400% with EtOAc, washed with 5% LiCl (4.times.8 mL),
saturated NH.sub.4Cl and brine. After drying with sodium sulfate,
the extracts were concentrated in vacuo and chromatographed on
silica gel using EtOAc in Heptane to give rise to desired product
(42.4 mg, 0.088 mmol). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.34NO.sub.4: 483.6. Found: 484.47, 485.49.
[1125] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydrobenzo[de]chromen-7-yl)-2,7-dimethy-
lquinolin-6-yl)acetic acid (102A) and
(S)-2-tert-butoxy-2-((S)-5-(2,3-dihydrobenzo[de]chromen-7-yl)-2,7-dimethy-
lquinolin-6-yl)acetic acid (102B): To a 3:1:1 (v/v/v)
THF-MeOH--H.sub.2O solution (10 mL) of (2S)-ethyl
2-tert-butoxy-2-(5-(2,3-dihydrobenzo[de]chromen-7-yl)-2,7-dimethylquinoli-
n-6-yl)acetate (42.4 mg, 0.088 mmol) was added LiOH (170 mg, 4.05
mmol) and the reaction allowed to stir overnight at 23.degree. C.
Hydrolysis was incomplete, so NaOH (.about.200 mg) was added and
the mixture stirred an additional 90 min at 23.degree. C. The
reaction was diluted 400% with EtOAc, washed with brine and dried
with sodium sulfate. Concentration in vacuo followed by PREP HPLC
purification gave rise to two atropisomer mixtures.
[1126] The first eluting atropisomer mixture was found to be 95:5
(ratio determined by NMR) mixture of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydrobenzo[de]chromen-7-yl)-2,7-dimethy-
lquinolin-6-yl)acetic acid (102A) as the major constituent and
(S)-2-tert-butoxy-2-((S)-5-(2,3-dihydrobenzo[de]chromen-7-yl)-2,7-dimethy-
lquinolin-6-yl)acetic acid as the impurity. .sup.1H-NMR: 400 MHz,
(CD.sub.3OD): .delta.: 8.02 (s, 1H); 7.94 (d, J=9.2 Hz, 1H); 7.56
(d, J=8.8 Hz, 1H); 7.31 (d, J=7.6 Hz, 1H); 7.26-7.20 (m, 2H); 70.07
(d, J=8.0 Hz, 1H); 7.02 (d, J=7.6 Hz, 1H); 5.20 (s, 1H); 4.55-4.48
(m, 2H); 2.92 (s, 3H); 2.86 (s, 3H); 1.04 (s, 9H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.29H.sub.30NO.sub.4: 456.5;
[1127] Found: 456.44.
[1128] The other atropisomer,
(S)-2-tert-butoxy-2-((S)-5-(2,3-dihydrobenzo[de]chromen-7-yl)-2,7-dimethy-
lquinolin-6-yl)acetic acid (102B), eluted later and was obtained as
a 2.61:1 (ratio determined by NMR) mixture as the major constituent
with
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydrobenzo[de]chromen-7-yl)-2,7-dimethy-
lquinolin-6-yl)acetic acid as the impurity. .sup.1H-NMR: 400 MHz,
(CD.sub.3OD): .delta.: 7.99 (s, 1H); 7.89 (d, J=8.4 Hz, 1H); 7.66
(d, J=8.0 Hz, 1H); 7.52 (d, J=8.8 Hz, 1H); 7.24-7.20 (m, 2H); 7.13
(d, J=8.0 Hz, 1H); 6.81 (d, J=8.0 Hz, 1H); 5.32 (s, 1H); 4.53-4.51
(m, 2H); 2.91 (2, 3H); 2.82 (s, 3H); 0.73 (s, 9H). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.29H.sub.30NO.sub.4: 456.5.
Found: 456.44.
Example 103
(2S)-2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[1,4]oxazino[2-
,3,4-ij]quinolin-8-yl)quinolin-6-yl)acetic acid (103)
##STR00238## ##STR00239##
[1130] Preparation of
5-bromo-1-(2-chloroethyl)-1,2,3,4-tetrahydroquinolin-8-ol: In a
round bottom flask, 3-chloropropanoic acid (8.44 g, 89.3 mmol, 20
eq.) was added to 5-bromoquinolin-8-ol (1 g, 4.46 mmol, 1 eq.) in
15 mL THF at 0.degree. C. NaBH.sub.4 (759 mg, 20 mmol, 4.5 eq.) was
added portionwise in 50 minutes at 0.degree. C. The reaction was
stirred at 0.degree. C. for 30 minutes then heated to 80.degree. C.
for 2 hours. The reaction was cooled down. Reaction mixture was
diluted with ethyl acetate and washed with brine, dried
(MgSO.sub.4), filtered, concentrated to give
5-bromo-1-(2-chloroethyl)-1,2,3,4-tetrahydroquinolin-8-ol crude.
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for C.sub.11H.sub.14BrClNO:
291.58. found: 292.0.
[1131] Preparation of
8-bromo-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinoline: The
above reaction crude was dissolved in 20 mL MeOH. 50 mL 2 N NaOH
aqueous solution was added. The reaction was stirred at room
temperature for 2 days. The reaction mixture was filtered. The
filtrate was concentrated and diluted with ethyl acetate and washed
with brine, purified by flash column chromatography (silica gel, 0
to 20% ethyl acetate/hexanes) to
8-bromo-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinoline as a
pale solid (374 mg, 33%). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd
for C.sub.11H.sub.13BrNO: 255.12. found: 255.41.
[1132] Preparation of
8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5,6,7-tetrahydro-2H-[1,-
4]oxazino[2,3,4-ij]quinoline: In a round bottom flask was charged
with 8-bromo-3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-ij]quinoline
(104 mg, 0.409 mmol, 1 eq.),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (208
mg, 0.818 mmol, 2 eq.), Pd(dppf)Cl.sub.2 (33 mg, 10%) and KOAc (201
mg, 5 eq.) in 3 mL dioxane. The reaction was heated at 80.degree.
C. under Ar overnight. The reaction was cooled down and diluted
with ethyl acetate and washed with brine, purified by flash column
chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to
8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5,6,7-tetrahydro-2H-[1,-
4]oxazino[2,3,4-ij]quinoline as a pale solid (146 mg, 100%).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.17H.sub.25BNO.sub.3: 302.19;
[1133] found: 302.2.
[1134] Preparation of (2S)-ethyl
2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-
-ij]quinolin-8-yl)quinolin-6-ypacetate: A Smith process vial was
charged with (S)-ethyl
2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (52 mg,
0.133 mmol, 1 eq.),
8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5,6,7-tetrahydro-2H-[1,-
4]oxazino[2,3,4-ij]quinoline (48 mg, 0.159 mmol.),
Pd(PPh.sub.3).sub.4 (15 mg, 10%) and flushed with nitrogen.
Dimethoxyethane (1.6 mL) and 2 M K.sub.2CO.sub.3 (0.24 mL, 0.48
mmol) was added. The reaction was heated in oil bath at 80.degree.
C. for 5 hours. The reaction mixture was diluted with ethyl acetate
and washed with brine, dried (MgSO.sub.4), filtered, concentrated
and purified by flash column chromatography (silica gel, 0 to 20%
ethyl acetate/hexanes) to give (2S)-ethyl
2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-
-ij]quinolin-8-yl)quinolin-6-yl)acetate as atropisomer mixture (39
mg, 60%). LCMS-ESI.sup.+: calcd for C.sub.30H.sub.37N.sub.2O.sub.4:
489.52 (M+H.sup.+). Found: 489.3.
[1135] Preparation of
(2S)-2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[1,4]oxazino[-
2,3,4-ij]quinolin-8-yl)quinolin-6-yl)acetic acid (103): A solution
of (2S)-ethyl
2-tert-butoxy-2-(2,7-dimethyl-5-(3,5,6,7-tetrahydro-2H-[1,4]oxazino[2,3,4-
-ij]quinolin-8-yl)quinolin-6-ypacetate (39 mg) and 2 M sodium
hydroxide (0.8 mL) in tetrahydrofuran (0.5 mL) and ethanol (2 mL)
was heated at 60.degree. C. for 8 hours. Reaction mixture was
diluted with ethyl acetate and washed with brine. The aqueous layer
was back-extracted with ethyl acetate and the combined organic
layer was dried (MgSO.sub.4), filtered, concentrated and purified
by reverse phase HPLC (Gemini, 5 to 100% ACN/H.sub.2O+0.1% TFA).
Product lyophilized to give an orange color powder (18 mg).
[1136] .sup.1H-NMR: 400 MHz, (CD.sub.3OD): .delta. 8.31, 8.20 (d,
d, 1H), 7.92, 7.88 (s, s, 1H), 7.70-7.67 (m, 1H), 6.74 (m, 1H),
6.42 (m, 1H), 5.42, 5.37 (s, s, 1H), 4.37 (m, 2H), 3.33 (m, 2H),
3.14 (m, 2H), 2.96 (s, 3H), 2.81, 2.78 (s, s, 3H), 2.40 (m, 1H),
1.96-1.78 (m, 3H), 1.17, 1.04 (s, s, 9H). LCMS-ESI.sup.+: calcd for
C.sub.28H.sub.33N.sub.2O.sub.4: 461.56 (M+H.sup.+). Found:
461.3.
Example 104
Compounds 104 and 105
[1137] Compounds 104 and 105 were prepared by similar methods as
shown in the above Examples.
TABLE-US-00002 Compound Number Compound Parent MW Measured mass 104
##STR00240## 432.35 432.1/434.1 105 ##STR00241## 454.95 455.6
Example 105
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(3-methylpyridin-2-yl)quinolin-6-yl)acetic acid (106)
##STR00242##
[1139]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(3-methylpyridin-2-yl)quinolin-6-yl)acetic acid (106)
was prepared following the procedure for
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(pyridin-2-yl)quinolin-6-yl)acetic acid of Example 80
except that 2-(dibutyl(pentypstannyl)-3-methylpyridine and a
catalytic amount of copper iodide was added to the first reaction.
.sup.1H-NMR: 400 MHz, (CD.sub.3CN) .delta.: 8.63 (d, J=4.8 Hz, 1H),
8.57 (d, J=4.8 Hz, 1H), 8.08 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.76
(d, J=8.8 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.48-7.43 (m, 3H), 5.25
(s, 1H), 4.62-4.56 (m, 2H), 3.44 (t, J=6.2 Hz, 2H), 2.74 (s, 3H),
2.64 (s, 3H), 0.93 (s, 9H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd
for C.sub.33H.sub.32N.sub.3O.sub.4: 534.23. found: 534.27.
Example 106
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(4-methylpyridin-3-yl)quinolin-6-yl)acetic acid (107)
##STR00243##
[1141]
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y-
l)-7-methyl-2-(4-methylpyridin-3-yl)quinolin-6-yl)acetic acid (107)
was prepared similarly to
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(3-methylpyridin-2-yDquinolin-6-yl)acetic acid of Example
105 using 3-(dibutyl(pentypstannyl)-4-methylpyridine instead of
2-(dibutyl(pentyl)stannyl)-3-methylpyridine. .sup.1H-NMR: 400 MHz,
(CD.sub.3CN) .delta.: 8.71 (s, 1H), 8.64-8.60 (m, 2H), 8.05 (s,
1H), 7.78 (d, J=6.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.49-7.42 (m,
3H), 7.27 (d, J=8.0 Hz, 1H), 5.25 (s, 1H), 4.63-4.59 (m, 2H), 3.46
(t, J=6.0 Hz, 2H), 2.74 (s, 3H), 2.63 (s, 3H), 0.94 (s, 9H).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.33H.sub.32N.sub.3O.sub.4: 534.23;
[1142] found: 534.34.
Example 107
(S)-2-tert-Butoxy-2-(2-(difluoromethyl)-7-methyl-5-(spiro[2.5]oct-5-en-6-y-
l)quinolin-6-yl)acetic acid (108)
##STR00244## ##STR00245##
[1144] Preparation of
(S)-2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacet-
ic acid:
(S)-2-(5-Bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-bu-
toxyacetic acid was isolated as a side product of the reaction
forming (S)-ethyl
2-(5-bromo-2-(difluoromethyl)-7-methylquinolin-6-yl)-2-tert-but-
oxyacetate from Example 99. LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd
C.sub.17H.sub.21BrNO.sub.4: 382.06. found: 382.72.
[1145] Preparation of (S)-methyl
2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate:
To a solution of
(S)-2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacet-
ic acid (3.6 g, 9.4 mmol) in anhydrous dichloromethane and methanol
(1:1, 20 mL) was added (trimethylsilyl)diazomethane (2 M in
hexanes, 5.17 mL, 10.34 mmol) and the reaction was stirred at room
temperature for three hours. An additional 2 mL of
(trimethylsilyl)diazomethane was added and stirred for 2 hours,
followed by an additional 1 mL of (trimethylsilyl)diazomethane for
1 hour, then 1 mL of (trimethylsilyl)diazomethane added and let go
overnight. An additional 3.5 mL of (trimethylsilyl)diazomethane
were added and stirred for 1 hour. The reaction was quenched with
30 mL of acetic acid and then stirred 15 minutes. The reaction was
concentrated under reduced pressure and then absorbed onto silica.
The crude reaction was purified by flash column chromatography
(silica gel, ethyl acetate/hexanes) to give a yellow foam (2.37 g).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd C.sub.18H.sub.23BrNO.sub.4:
396.07. found: 396.71.
[1146] Preparation of (S)-methyl
2-(5-bromo-2-(difluoromethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate-
: Prepared similarly to (S)-ethyl
2-(5-bromo-2-(difluoromethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate
of Example 99 using (S)-methyl
2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate
instead of (S)-ethyl
2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate.
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd
C.sub.18H.sub.2113rF.sub.2NO.sub.3: 416.06. found: 416.75.
[1147] Preparation of (S)-methyl
2-tert-butoxy-2-(2-(difluoromethyl)-7-methyl-5-(spiro[2.5]oct-5-en-6-yl)q-
uinolin-6-ypacetate: To a solution of (S)-methyl
2-(5-bromo-2-(difluoromethyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate
(50 mg, 0.12 mmol) in tetrahydrofuran and water (1 mL and 0.1 mL)
was added
4,4,5,5-tetramethyl-2-(spiro[2.5]oct-5-en-6-yl)-1,3,2-dioxaborolane
(42 mg, 0.18 mmol), potassium phosphate (84 mg, 0.36 mmol) and
(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylph-
enyl)]palladium(II) chloride methyl-t-butyl ether adduct, (SPhos)
palladium(II) phenethylamine chloride (8.1 mg, 0.012 mmol). The
reaction was heated in a microwave reactor at 110.degree. C. for 30
minutes and then absorbed onto silica. The crude reaction was
purified by flash column chromatography (silica gel, ethyl
acetate/hexanes) to give a clear white oil (44.7 mg).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd
C.sub.26H.sub.32F.sub.2NO.sub.3: 444.23. found: 444.54.
[1148] Preparation of
(S)-2-tert-butoxy-2-(2-(difluoromethyl)-7-methyl-5-(spiro[2.5]oct-5-en-6--
yl)quinolin-6-yl)acetic acid (108): To a solution of (S)-methyl
2-tert-butoxy-2-(2-(difluoromethyl)-7-methyl-5-(spiro[2.5]oct-5-en-6-yl)q-
uinolin-6-yl)acetate (44.7 mg, 0.101 mmol) in
tetrahydrofuran:methanol:water (2:2:1, 2 mL) was added lithium
hydroxide (12 mg, 0.504 mmol) and the reaction was heated to
50.degree. C. overnight. The reaction was diluted with acetonitrile
and purified by reverse phase HPLC (Gemini, 15 to 95
ACN/H.sub.2O+0.1% TFA) and the desired product was lyophilized to
give a white powder (29.2 mg). .sup.1H-NMR: 400 MHz, (CD.sub.3CN)
.delta.: 8.49 (d, J=8.8 Hz, 1H), 7.85 (s, 1H), 7.69 (d, J=8.4 Hz,
1H), 6.84 (t, =55.2 Hz, 1H), 5.93 (s, 1H), 5.68 (s, 1H), 2.67 (m,
1H), 2.62 (s, 3H), 2.46 (m, 1H), 2.28-2.24 (m, 2H), 1.66 (m, 2H),
1.23 (s, 9H), 0.54-0.40 (m, 4H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calcd for C.sub.25H.sub.30F.sub.2NO.sub.3: 430.21. found:
430.32.
Example 108
(S)-2-tert-butoxy-2-((R)-2-(cyclopropylmethoxy)-5-(2,3-dihydropyrano[4,3,2-
-de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (109)
##STR00246## ##STR00247##
[1150] Preparation of
(S)-2-tert-butoxy-2-((R)-2-(cyclopropylmethoxy)-5-(2,3-dihydropyrano[4,3,-
2-de]quinolin-7-yl)-7-methylquinolin-6-yl)ethyl pivalate: To a
solution of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (100 mg, 0.189
mmol) and silver carbonate (156 mg, 0.567 mmol) in
benzene:dichloroethane (1:1, 1 mL) was added
(bromomethyl)cyclopropane (0.037 mL, 0.38 mmol) and the reaction
was heated at 45.degree. C. overnight. The crude reaction was
purified by flash column chromatography (silica gel, ethyl
acetate/hexanes) to give a brown oil (65.8 mg). LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calcd for C.sub.36H.sub.43N.sub.2O.sub.5:
583.31. found: 583.67.
[1151] Preparation of
(S)-2-tert-butoxy-2-((R)-2-(cyclopropylmethoxy)-5-(2,3-dihydropyrano[4,3,-
2-de]quinolin-7-yl)-7-methylquinolin-6-yl)ethanol: To a solution of
(S)-2-tert-butoxy-2-((R)-2-(cyclopropylmethoxy)-5-(2,3-dihydropyrano[4,3,-
2-de]quinolin-7-yl)-7-methylquinolin-6-yl)ethyl pivalate (65.8 mg,
0.113 mmol) in tetrahydrofuran:methanol (5:1, 3 mL) was added 1 M
sodium hydroxide (3 mL) and the reaction was heated at 45.degree.
C. overnight. The reaction was diluted with water, extracted with
ethyl acetate, washed with brine and dried over sodium sulfate. The
solution was concentrated and then co-evaporated 2 times with
acetonitrile to give a brown oil (55 mg). LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calcd for C.sub.31H.sub.35N.sub.2O.sub.4: 499.25.
found: 499.54.
[1152] Preparation of
(S)-2-tert-butoxy-2-((R)-2-(cyclopropylmethoxy)-5-(2,3-dihydropyrano[4,3,-
2-de]quinolin-7-yl)-7-methylquinolin-6-yl)acetic acid (109): To a
solution of
(S)-2-tert-butoxy-2-((R)-2-(cyclopropylmethoxy)-5-(2,3-dihydropyrano[4-
,3,2-de]quinolin-7-yl)-7-methylquinolin-6-yl)ethanol (55 mg, 0.11
mmol) in wet acetonitrile (2 mL) was added
CrO.sub.3/H.sub.5IO.sub.6 (0.4 M, 1.65 mL, 0.662 mmol) at 0.degree.
C. The reaction was stirred for 3 hours and then diluted with
methanol. The crude material was purified by reverse phase HPLC
(Gemini, 15 to 65% ACN/H.sub.2O=0.1% TFA) and the desired product
was lyophilized to give a yellow powder (18.1 mg). .sup.1H-NMR: 400
MHz, (CD.sub.3CN) .delta.: 8.58 (d, J=5.2 Hz, 1H), 7.76 (s, 1H),
7.71 (d, J=8.0 Hz, 1H), 7.55 (d, J=5.2 Hz, 1H), 7.30 (d, J=8.0 Hz,
1H), 7.13 (d, J=9.2 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.14 (s, 1H),
4.64-4.58 (m, 2H), 4.28 (d, J=6.8 Hz, 2H), 3.49 (t, J=5.6 Hz, 2H),
2.67 (s, 3H), 1.33-1.28 (m, 1H), 0.91 (s, 9H), 0.60-0.57 (m, 2H),
0.40-0.37 (m, 2H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calcd for
C.sub.31H.sub.33N.sub.2O.sub.5: 513.23. found: 513.31.
Example 109
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-me-
thyl-2-(trifluoromethyl)quinolin-6-yl)acetic acid (110)
##STR00248##
[1154] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethyl)quinolin-6-yl)ethyl pivalate:
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethyl)quinolin-6-yl)ethyl pivalate (72 mg) was
prepared in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethyl pivalate (7H) of example 7J except using
2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride
instead of 4-chlorophenylboronic acid. LCMS-ESI.sup.+ (m/z):
[M+H].sup.+ calc'd for C.sub.33H.sub.36F.sub.3N.sub.2O.sub.4:
581.2;
[1155] Found: 581.1.
[1156] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethyl)quinolin-6-yl)ethanol:
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethyl)quinolin-6-yl)ethanol (60 mg) was prepared
in a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethanol (7I) of example 7J except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethyl)quinolin-6-yl)ethyl pivalate instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethyl pivalate (711).
[1157] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calc'd for
C.sub.28H.sub.28F.sub.3N.sub.2O.sub.3: 497.2. Found: 497.0.
[1158] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethyl)quinolin-6-yl)acetic acid (110):
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethyl)quinolin-6-yl)acetic acid was prepared in
a similar manner as compound
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)acetic acid (7J) of example 7J except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethyl)quinolin-6-yl)ethanol instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethanol (7I). .sup.1H-NMR 400 MHz, (CD.sub.3OD) 8.70 (d,
J=5.5 Hz, 1H), 8.26 (s, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.80 (d, J=5.5
Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.46 (d,
J=7.8 Hz, 1H), 5.28 (s, 1H), 4.74 (m, 2H), 3.66 (t, J=5.5 Hz, 2H),
2.88 (s, 3H), 0.95 (s, 9H); LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calc'd for C.sub.28H.sub.26F.sub.3N.sub.2O.sub.4: 511.20. Found:
511.10.
Example 110
(S)-2-((R)-2-Acetyl-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methylq-
uinolin-6-yl)-2-tert-butoxyacetic acid (111)
##STR00249## ##STR00250##
[1160] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-2-(1-ethoxyvinyl)-7-methylquinolin-6-yl)ethyl
pivalate: (S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-2-(1-ethoxyvinyl)-7-methylquinolin-6-yl)ethyl
pivalate (46 mg) was prepared in a similar manner as
5-bromo-7-methyl-6-vinylquinoline (8E) of example 8L except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-m-
ethyl-2-(trifluoromethylsulfonyloxy) quinolin-6-yl)ethyl pivalate
and tributyl(1-ethoxyvinyl)stannane instead of
5-bromo-7-methylquinolin-6-yl trifluoromethanesulfonate (8D) and
tributyl(vinyl)stannane.
[1161] LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calc'd for
C.sub.36H.sub.43N.sub.2O.sub.5: 583.30. Found: 583.30.
[1162] Preparation of
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
1-ethoxyvinyl)-7-methylquinolin-6-yl)ethanol:
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
1-ethoxyvinyl)-7-methylquinolin-6-yeethanol (16 mg) was prepared in
a similar manner as compound
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethanol (71) of example 7J except using
(S)-2-tert-butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
1-ethoxyvinyl)-7-methylquinolin-6-yl)ethyl pivalate instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethyl pivalate (7H). LCMS-ESI.sup.+ (m/z): [M+H].sup.+
calc'd for C.sub.31H.sub.35N.sub.2O.sub.4: 499.31. Found:
499.30.
[1163] Preparation of
1-((R)-6-((S)-1-tert-butoxy-2-hydroxyethyl)-5-(2,3-dihydropyrano[4,3,2-de-
]quinolin-7-yl)-7-methylquinolin-2-yl)ethanone:
(S)-2-tert-Butoxy-2-((R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-(-
1-ethoxyvinyl)-7-methylquinolin-6-yl)ethanol (16 mg) was dissolved
in acetone (1.6 ml), and aqueous hydrochloric acid (2 N, 0.16 ml)
was added. The mixture was stirred for 12 hours, and diluted with
dichloromethane. The organic solution was washed with water and
brine, and dried over sodium sulfate. Concentration and
purification with flash column chromatography (silica gel,
hexane/EtOAc) gave
1-((R)-6-((S)-1-tert-butoxy-2-hydroxyethyl)-5-(2,3-dihydropyrano[4,3,2-de-
]quinolin-7-yl)-7-methylquinolin-2-yl)ethanone (15 mg).
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calc'd for
C.sub.29H.sub.31N.sub.2O.sub.4: 471.2. Found: 471.1.
[1164] Preparation of
(S)-2-((R)-2-acetyl-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-
quinolin-6-yl)-2-tert-butoxyacetic acid (111):
(S)-2-((R)-2-Acetyl-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-methyl-
quinolin-6-yl)-2-tert-butoxyacetic acid (7.2 mg) was prepared in a
similar manner as compound
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)acetic acid (7J) of example 7J except using
1-((R)-6-((S)-1-tert-butoxy-2-hydroxyethyl)-5-(2,3-dihydropyrano[4,3,2-de-
]quinolin-7-yl)-7-methylquinolin-2-ypethanone instead of
(S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethyl)quino-
lin-6-yl)ethanol (7I). .sup.1H-NMR 400 MHz (CD.sub.3OD) .delta.
8.69 (d, J=6.3 Hz, 1H), 8.29 (s, 1 FI), 7.89-7.79 (m, 3H), 7.53 (d,
J=9.0 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 5.28 (s, 1H), 4.70 (m, 2H),
3.66 (t, J=5.5 Hz, 2H), 2.86 (s, 3H), 2.82 (s, 3H), 0.95 (s, 9H);
LCMS-ESI.sup.+ (m/z): [M+H].sup.+ calc'd for
C.sub.29H.sub.29N.sub.2O.sub.5: 485.2. Found: 485.1; LCMS-ESI.sup.+
(m/z): [M-H].sup.+ calc'd for C.sub.29H.sub.27N.sub.2O.sub.5:
483.2. Found: 483.2.
Example 111
(2S)-2-tert-Butoxy-2-((5 R)-5-(2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)-2-(1-hydroxyethyl)-7-methylquinolin-6-yl)acetic acid
(112)
##STR00251##
[1166] Preparation of
(2S)-2-tert-Butoxy-2-((5R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-
-(1-hydroxyethyl)-7-methylquinolin-6-yl)acetic acid (112): To the
solution of
(S)-2-((R)-2-acetyl-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-met-
hylquinolin-6-yl)-2-tert-butoxyacetic acid (4.4 mg) im methanol
(0.2 ml) at 0.degree. C. was added sodium borohydride (1 mg). The
mixture was warmed to 25.degree. C. and stirred for one hour. The
mixture was quenched with water, and methanol was removed under
reduced pressure. Filtration and purification by reverse phase HPLC
(0.1% TFA/CH.sub.3CN-0.1% TFA/H.sub.2O) gave
(2S)-2-tert-butoxy-2-((5R)-5-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-
-(1-hydroxyethyl)-7-methylquinolin-6-yl)acetic acid (112) (0.5 mg).
.sup.1H-NMR 400 MHz (CD.sub.3OD) .delta. 8.64 (d, J=5.2 Hz, 1H),
8.25 (s, 1H), 7.90-7.87 (m, 1H), 7.74 (m, 1H), 7.66-7.60 (m, 2H),
7.36-7.34 (m, 1H), 5.26 (s, 1H), 5.20 (m, 1H), 4.66 (m, 2H), 3.55
(m, 2H), 2.89 (s, 3H), 1.60 (m, 3H), 0.92 (s, 9H); LCMS-ESI.sup.+
(m/z): [M+H].sup.+ calc'd for C.sub.29H.sub.31N.sub.2O.sub.5:
487.2. Found: 487.2.
Example 112
[1167] The following illustrate representative pharmaceutical
dosage forms, containing a compound of formula I (`Compound X`),
for therapeutic or prophylactic use in humans.
TABLE-US-00003 (i) Tablet 1 mg/tablet Compound X = 100.0 Lactose
77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline
cellulose 92.5 Magnesium stearate 3.0 300.0
TABLE-US-00004 (ii) Tablet 2 mg/tablet Compound X = 20.0
Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch
glycolate 15.0 Magnesium stearate 5.0 500.0
TABLE-US-00005 (iii) Capsule mg/capsule Compound X = 10.0 Colloidal
silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0
Magnesium stearate 3.0 600.0
TABLE-US-00006 (iv) Injection 1 (1 mg/mL) mg/mL Compound X = (free
acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium
phosphate 0.7 Sodium chloride 4.5 1.0N Sodium hydroxide solution
q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1
mL
TABLE-US-00007 (v) Injection 2 (10 mg/mL) mg/mL Compound X = (free
acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium
phosphate 1.1 Polyethylene glycol 400 200.0 01N Sodium hydroxide
solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s.
ad 1 mL
TABLE-US-00008 (vi) Aerosol mg/can Compound X = 20.0 Oleic acid
10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane
10,000.0 Dichlorotetrafluoroethane 5,000.0
The above formulations may be obtained by conventional procedures
well known in the pharmaceutical art.
[1168] All publications, patents, and patent documents are
incorporated by reference herein, as though individually
incorporated by reference. The invention has been described with
reference to various specific and preferred embodiments and
techniques. However, it should be understood that many variations
and modifications may be made while remaining within the spirit and
scope of the invention.
* * * * *